阻断病毒进入细胞的抗HIV-1药物设计
|
摘要
1983年,科学家Barre-Sinoussi等首次确认1型人类免疫缺陷病毒(Human Immunodeficiency virus 1, HIV-1)是引起获得性免疫缺陷综合症(Acquired immunodeficiency syndrome, AIDS)的病原体。自从1981年6月发现首例艾滋病患者到2007年底,这种疾病已导致超过两千万人死亡。尽管现有的药物以及高效抗逆转录病毒联合疗法(Highly Active Antiretroviral Therapy, HAART)的应用改善了病人临床治疗效果,但无法根除病毒、耐药性病毒株的出现以及毒副作用是其难以克服的困难。迄今为止,疫苗的研制仍未获得成功,因此针对新靶点研发安全高效的抗HIV药物非常紧迫。2003年上市的Fuzeon(T-20)证明了阻断病毒进入细胞可抑制艾滋病,病毒进入细胞过程成为当前药物设计研究的热点。众所周知,新药研发是一项耗资巨大的工程,为了提高研发效率、缩短研发周期、降低成本,计算机辅助药物设计(Computer-aided drug design, CADD)方法近年来被广泛地应用于现代新药开发中。该方法主要分为两类:基于结构的药物设计以及基于配体的药物设计。本论文结合CADD方法,以设计新型抗艾滋病药物为目的,以病毒进入细胞过程为研究对象,从配体和受体出发进行了一系列应用基础研究工作。论文内容主要包括以下几个方面:
(1) HIV-1包膜蛋白gp120与抑制剂BMS-378806结合模式的研究
BMS-378806是新发现的可有效抑制gp120蛋白与CD4受体结合的小分子,它与gp120的结合模式尚未阐明。本论文联合使用分子对接(AutoDock 3.0)和分子动力学(Molecular dynamics, MD)模拟方法,探索了BMS-378806与gp120蛋白的结合模式。对接能较低的结合模式Mode I和Mode II被选为代表构象。进一步的复合物MD模拟表明,Mode II中小分子与gp120结合更为稳定。分析Mode II的动力学平均结构并和实验结果进行对照,发现小分子氮杂吲哚与Trp427残基的接近可能导致了环上C-4位置取代的敏感性。在Phe43口袋内部的残基向大侧链残基的突变,如S375W和T257R可能会对结合造成空间位阻。口袋中的其他残基Ser256、Thr257、Asn425、Met426和Val430与小分子有较强的相互作用。复合物的平均结构与残基突变实验较为吻合。BMS-378806与结合态gp120的作用模式类似于CD4上Phe43残基与gp120的结合。模拟结果从原子水平上给出了这类抑制剂的结合模式。
(2)以HIV-1跨膜蛋白gp41为靶点的抑制剂设计
(a)基于配体的药效团模型构建
根据目前已知的抑制跨膜蛋白gp41六螺旋结构形成的小分子结构,用GASP软件构建了基于配体的药效团模型。挑选的模型Model 01由两个疏水特征、两对氢键受体特征和一对氢键给体特征组成,将活性分子与药效团模型叠合发现,分子中的苯环、吡咯环等对应了模型中的疏水特征,羧基、羟基等对应了模型的氢键受体和给体特征。
(b)结合模式研究和基于受体的药效团模型构建
用分子对接的手段研究已有的小分子抑制剂与gp41五螺旋结构的结合模式,并根据分子对接的结果,进行了基于受体的药效团模型构建,模型包括四个疏水特征,三个氢键受体特征和一个氢键给体特征。
(c)药效团模型的验证
通过对比基于配体的药效团模型Model 01、小分子的结合模式及基于受体的药效团模型,发现三者之间比较一致,基于配体结构得到的模型Model 01可认为是基于受体的药效团模型的一部分。从ACDSC库中随机挑选部分分子,并加入已知活性抑制剂构成测试数据库,使用该库对Model 01进行筛选能力测试,发现该模型可有效的将活性化合物挑选出来(富集度为5.04)。
(d)针对gp41的虚拟筛选
设计了综合考虑已知配体信息和受体结构信息的针对gp41的虚拟筛选策略。对包括CMC、ACDSC、NCI、MDDR以及中国中草药数据库(CHDD)在内的总共250万个分子进行了虚拟筛选、毒性预测和象药性分析,挑选出36个小分子化合物,已合成两个化合物,在体外细胞水平实验上表现出一定的抑制HIV-1 IIIB型病毒感染的能力。
(e) NB-2分子的结构优化
以gp41的五螺旋晶体结构为靶点,使用从头设计方法(LeapFrog)在已知象药性小分子抑制剂NB-2的基础上对其结构进行了优化,并用分子对接程序对新分子进行了结合模式和结合自由能预测。新分子的计算结合自由能普遍低于NB-2分子,化合物的合成正在进行中。
(3) CCR5受体拮抗剂的设计
(a)可预测活性的药效团模型构建
用已知的吡咯烷与正丁烷类CCR5拮抗剂的结构和活性信息构建了一个三维药效团模型。最好的药效团模型(Hypo 1)由两个正离子化特征和三个疏水特征组成,训练集预测的相关系数为0.924,null cost值与total cost值的差异为63.67 bits。用该模型预测了由74个分子组成的测试集活性,结果表明该模型可以提供较好的活性预测结果(R = 0.703)。使用该模型预测了虚拟组合化学库中小分子的活性值,挑选出部分预测活性较好的分子进入到合成阶段。
(b) CoMFA和CoMSIA模型的构建
选择72个吡咯烷分子作为训练集,39个吡咯烷分子作为测试集,进行了CoMFA(Comparative Molecular Field Analysis)和CoMSIA(Comparative Molecular Similarity Indices Analysis)模型构建。最佳CoMFA模型(CoMFA2)的非交叉验证回归系数r2为0.952,交叉验证回归系数q2为0.637,并可对测试集分子作出较好的预测(相关系数R = 0.785)。最佳CoMSIA模型(CoMSIA2)的非交叉验证回归系数r2为0.958,交叉验证回归系数q2为0.677,对测试集分子作出了较好的预测(相关系数R = 0.806)。同时等势面图提供了立体场、静电场、氢键场和疏水场的可视化图像。本研究可为这类化合物的结构优化提供线索。
本文以HIV-1病毒进入细胞过程的关键蛋白gp120、gp41和CCR5为靶点,使用分子模拟的手段对抑制剂与蛋白的结合模式、药效团模型以及定量构效关系进行了一系列的研究。获得了可解释实验结果的抑制剂与蛋白的合理结合模式,可有效挑选活性分子的药效团模型以及具有一定预测能力的定量构效关系模型,设计了一批针对不同靶点的新化合物,部分分子被合成并测定具有抗病毒活性。本文的研究工作可为新型抗艾滋病药物的开发提供有用信息。
In 1983, Barre-Sinousi et al. identified the human immunodeficiency virus (HIV-1) as the source of infection of acquired immunodeficiency syndrome (AIDS) for the first time. Since the first patient of AIDS was discovered in June 1981, this fatal disease has taken over 20 million people away. Although the application of current drugs and highly active antiretroviral therapy has achieved great successes, there still exist a number of difficulties, such as the unavailable eradication of the virus, the emergence of drug resistant virus and the strong side effects. Up till now, the medical research on vaccine also failed to break through. Therefore, it is of great urgency to design the novel drugs with safety and effectiveness against the new targets in the life cycle of HIV-1. The Fuzeon (T-20) which came into the market as an anti-HIV-1 drug in 2003 proved the entry process as potential and effective targets. Recently, it also becomes the focus of the medical research for the purpose to discover safe and effective inhibitors dealing with the entry stage of HIV-1 infection. It is well known that the discovery of new drugs is quite a costly and time consuming task. The application of computer-aided drug design (CADD) in the process of drug discovery is expected to save both money and time. In recent years, it is widely used in current drug discovery research. CADD is commonly separated into two general categories: Structure-Based Drug Design and Ligand-Based Drug Design. In this thesis, a series of research work has been done based on the ligand and receptor structures by using the CADD methods to study the entry process of the virus infection, with the aim to design the lead compounds against AIDS. The content of the thesis contain the following major aspects:
(1) Study on binding mode between BMS-378806 and HIV-1 envelope protein - gp120
BMS-378806 is a newly discovered small molecule that effectively blocks the binding of CD4 with gp120. The binding mode of this type of inhibitors remains unknown. AutoDock 3.0 in conjunction with molecular dynamics (MD) simulation was used to explore the binding mode between BMS-378806 and gp120. Two structures, Mode I and Mode II, with the lowest docking energy were selected as different representative binding modes. The analysis for the MD simulation data of the complex indicates that the binding of BMS-348806 with gp120 in Mode II is more stable. The average structure of Mode II was analyzed and compared with the experimental data. The sensitive of C-4 substitution on the azaindole ring may result from its occurence in the vicinity of Trp427. The Large side chain mutations inside the Phe43 cavity, such as S375W and T257R mutation, make steric hindrance for the binding. Other reisdues in the cavity such as Ser256, Thr257, Asn425, Met426 and VAL430 have considerable interactions with the small molecule. The average structure of the complex is consistent with the experimental data of mutation. The binding mode between BMS-378806 and the bounded state gp120 is similar to the binding of Phe43 in CD4 with gp120. The simulation results give an atomic insight to the possible binding mode of this kind of inhibitors.
(2) Inhibitor design targeting to HIV-1 transmembrane protein - gp41
(a) Pharmacophore model construction based on ligands’structures
The software of GASP was used to generate ligand-based pharmacophore models on the basis of the identified structure information of active inhibitors interfering with the six helix bundle formation of gp41. The selected model - Model 01 was comprised of two hydrophobic features, two pairs of hydrogen bond acceptor features and one pair of hydrogen bond donor feature. The mapping of active molecules to the model showed that the hydrophobic features represented the phenyl group or pyrrole group, and the hydrogen bond features represented the hydroxyl group or carboxyl group.
(b) Binding modes research and pharmacophore model construction based on receptor structures
The binding modes of the known inhibitors with the 5-helix gp41 were obtained by using the molecule docking methods. The acceptor-based pharmacophore model was constructed according to the docking results. It is composed of four hydrophobic features, three hydrogen bond acceptor features and one hydrogen bond donor feature.
(c) Pharmacophore model validation
By comparison of the ligand-based pharmacophore model (Model 01), the binding modes of the inhibitors and the acceptor-based pharmacophore model, they all turned out a sort of consistency. The ligand-based pharmacophore model seemed to be a subset of the acceptor-based pharmacophore model, which is necessary for the activity. The filter property of the model was validated by a test database which was composed by molecules randomly selected from the ACDSC database and the known inhibitors. The results show that the model could filter out the active molecules efficiently with an enrichment factor of 5.04.
(d) Virtual screening target to gp41
A virtual screening strategy was designed to combine both the ligand and the receptor structure information. About 2,500,000 molecules from CMC, ACDSC, NCI, MDDR and CHDD were screened. The toxicity and drug-like properties were also estimated. Thirty six molecules were selected finally and two of them were synthesized. Both of the compounds showed the ability to inhibit the infection of the HIV-1 IIIB virus in vitro.
(e) Structural optimization based on NB-2
The de novo drug design method ( LeapFrog ) was used to optimize structure of NB-2 targeting the 5-helix structure of gp41. The docking method was adopted to recalculate the binding modes and the binding free energy of the new compounds. It was found that the binding free energy of new molecules were low than that of NB-2.
The synthesis experiments are undertaken on the way.
(3) Inhibitor design targeting to CCR5
(a) Construction of predicable pharmacophore model
A three dimensional pharmacophore model was developed for a considerable number of pyrrolidine based and butane-based chemokine (C-C motif) receptor 5 (CCR5) antagonists. The most predictive pharmacophore model (Hypo 1), consisting of two positive ionizable points and three hydrophobic groups, had a correlation of 0.924 for the training set, and a cost difference of 63.67 bits between the null cost and the total cost. The model was applied to predict the activity of 74 compounds as a test set with a correlation factor of 0.703. The results indicated that the model was able to provide accurate activity prediction for novel antagonist design. It has been employed to filter a combinatorial database, and the molecules with good predicted activities were selected into the synthesis experiments.
(b) Construction of CoMFA and CoMSIA model
A series of 1,3,4-trisubstituted pyrrolidine-based CCR5 receptor antagonists was taken as our target to construct CoMFA (Comparative Molecular Field Analysis) and CoMSIA (Comparative Molecular Similarity Indices Analysis) models. The training set and test set consisting of 72 and 39 selected molecules, respectively. For the best CoMFA model (CoMFA2), the conventional correlation coefficient r2 = 0.952, the cross-validated coeffient q2 = 0.637, and the correlation factor on the test set prediction R = 0.785, while for the best CoMSIA model (CoMSIA2), r2 = 0.958, q2 = 0.677, and R = 0.806. Furthermore the contour map also provides a visual representation for the contributions of steric, electrostatic, hydrogen-bond and hydrophobic fields. The study could provide useful information for structure optimization of this kind of compounds.
In this paper, a series of research work, including binding mode prediction, pharmacophore model construction and QSAR (Quantitative structure-activity relationship) analysis has been done against the key proteins (gp120, gp41, CCR5) involved in the entry of HIV-1. A binding mode of BMS-378806 with gp120 which is consistent with the experimental data as well as effective pharmacophore models based on gp41 inhibitors and predictable QSAR models based on CCR5 antagonists were achieved. The new compounds targeting to different proteins were designed and a part of them were synthesized and proved to be active. These works may benefit the development of anti-AIDS drug candidates.
(1) HIV-1包膜蛋白gp120与抑制剂BMS-378806结合模式的研究
BMS-378806是新发现的可有效抑制gp120蛋白与CD4受体结合的小分子,它与gp120的结合模式尚未阐明。本论文联合使用分子对接(AutoDock 3.0)和分子动力学(Molecular dynamics, MD)模拟方法,探索了BMS-378806与gp120蛋白的结合模式。对接能较低的结合模式Mode I和Mode II被选为代表构象。进一步的复合物MD模拟表明,Mode II中小分子与gp120结合更为稳定。分析Mode II的动力学平均结构并和实验结果进行对照,发现小分子氮杂吲哚与Trp427残基的接近可能导致了环上C-4位置取代的敏感性。在Phe43口袋内部的残基向大侧链残基的突变,如S375W和T257R可能会对结合造成空间位阻。口袋中的其他残基Ser256、Thr257、Asn425、Met426和Val430与小分子有较强的相互作用。复合物的平均结构与残基突变实验较为吻合。BMS-378806与结合态gp120的作用模式类似于CD4上Phe43残基与gp120的结合。模拟结果从原子水平上给出了这类抑制剂的结合模式。
(2)以HIV-1跨膜蛋白gp41为靶点的抑制剂设计
(a)基于配体的药效团模型构建
根据目前已知的抑制跨膜蛋白gp41六螺旋结构形成的小分子结构,用GASP软件构建了基于配体的药效团模型。挑选的模型Model 01由两个疏水特征、两对氢键受体特征和一对氢键给体特征组成,将活性分子与药效团模型叠合发现,分子中的苯环、吡咯环等对应了模型中的疏水特征,羧基、羟基等对应了模型的氢键受体和给体特征。
(b)结合模式研究和基于受体的药效团模型构建
用分子对接的手段研究已有的小分子抑制剂与gp41五螺旋结构的结合模式,并根据分子对接的结果,进行了基于受体的药效团模型构建,模型包括四个疏水特征,三个氢键受体特征和一个氢键给体特征。
(c)药效团模型的验证
通过对比基于配体的药效团模型Model 01、小分子的结合模式及基于受体的药效团模型,发现三者之间比较一致,基于配体结构得到的模型Model 01可认为是基于受体的药效团模型的一部分。从ACDSC库中随机挑选部分分子,并加入已知活性抑制剂构成测试数据库,使用该库对Model 01进行筛选能力测试,发现该模型可有效的将活性化合物挑选出来(富集度为5.04)。
(d)针对gp41的虚拟筛选
设计了综合考虑已知配体信息和受体结构信息的针对gp41的虚拟筛选策略。对包括CMC、ACDSC、NCI、MDDR以及中国中草药数据库(CHDD)在内的总共250万个分子进行了虚拟筛选、毒性预测和象药性分析,挑选出36个小分子化合物,已合成两个化合物,在体外细胞水平实验上表现出一定的抑制HIV-1 IIIB型病毒感染的能力。
(e) NB-2分子的结构优化
以gp41的五螺旋晶体结构为靶点,使用从头设计方法(LeapFrog)在已知象药性小分子抑制剂NB-2的基础上对其结构进行了优化,并用分子对接程序对新分子进行了结合模式和结合自由能预测。新分子的计算结合自由能普遍低于NB-2分子,化合物的合成正在进行中。
(3) CCR5受体拮抗剂的设计
(a)可预测活性的药效团模型构建
用已知的吡咯烷与正丁烷类CCR5拮抗剂的结构和活性信息构建了一个三维药效团模型。最好的药效团模型(Hypo 1)由两个正离子化特征和三个疏水特征组成,训练集预测的相关系数为0.924,null cost值与total cost值的差异为63.67 bits。用该模型预测了由74个分子组成的测试集活性,结果表明该模型可以提供较好的活性预测结果(R = 0.703)。使用该模型预测了虚拟组合化学库中小分子的活性值,挑选出部分预测活性较好的分子进入到合成阶段。
(b) CoMFA和CoMSIA模型的构建
选择72个吡咯烷分子作为训练集,39个吡咯烷分子作为测试集,进行了CoMFA(Comparative Molecular Field Analysis)和CoMSIA(Comparative Molecular Similarity Indices Analysis)模型构建。最佳CoMFA模型(CoMFA2)的非交叉验证回归系数r2为0.952,交叉验证回归系数q2为0.637,并可对测试集分子作出较好的预测(相关系数R = 0.785)。最佳CoMSIA模型(CoMSIA2)的非交叉验证回归系数r2为0.958,交叉验证回归系数q2为0.677,对测试集分子作出了较好的预测(相关系数R = 0.806)。同时等势面图提供了立体场、静电场、氢键场和疏水场的可视化图像。本研究可为这类化合物的结构优化提供线索。
本文以HIV-1病毒进入细胞过程的关键蛋白gp120、gp41和CCR5为靶点,使用分子模拟的手段对抑制剂与蛋白的结合模式、药效团模型以及定量构效关系进行了一系列的研究。获得了可解释实验结果的抑制剂与蛋白的合理结合模式,可有效挑选活性分子的药效团模型以及具有一定预测能力的定量构效关系模型,设计了一批针对不同靶点的新化合物,部分分子被合成并测定具有抗病毒活性。本文的研究工作可为新型抗艾滋病药物的开发提供有用信息。
In 1983, Barre-Sinousi et al. identified the human immunodeficiency virus (HIV-1) as the source of infection of acquired immunodeficiency syndrome (AIDS) for the first time. Since the first patient of AIDS was discovered in June 1981, this fatal disease has taken over 20 million people away. Although the application of current drugs and highly active antiretroviral therapy has achieved great successes, there still exist a number of difficulties, such as the unavailable eradication of the virus, the emergence of drug resistant virus and the strong side effects. Up till now, the medical research on vaccine also failed to break through. Therefore, it is of great urgency to design the novel drugs with safety and effectiveness against the new targets in the life cycle of HIV-1. The Fuzeon (T-20) which came into the market as an anti-HIV-1 drug in 2003 proved the entry process as potential and effective targets. Recently, it also becomes the focus of the medical research for the purpose to discover safe and effective inhibitors dealing with the entry stage of HIV-1 infection. It is well known that the discovery of new drugs is quite a costly and time consuming task. The application of computer-aided drug design (CADD) in the process of drug discovery is expected to save both money and time. In recent years, it is widely used in current drug discovery research. CADD is commonly separated into two general categories: Structure-Based Drug Design and Ligand-Based Drug Design. In this thesis, a series of research work has been done based on the ligand and receptor structures by using the CADD methods to study the entry process of the virus infection, with the aim to design the lead compounds against AIDS. The content of the thesis contain the following major aspects:
(1) Study on binding mode between BMS-378806 and HIV-1 envelope protein - gp120
BMS-378806 is a newly discovered small molecule that effectively blocks the binding of CD4 with gp120. The binding mode of this type of inhibitors remains unknown. AutoDock 3.0 in conjunction with molecular dynamics (MD) simulation was used to explore the binding mode between BMS-378806 and gp120. Two structures, Mode I and Mode II, with the lowest docking energy were selected as different representative binding modes. The analysis for the MD simulation data of the complex indicates that the binding of BMS-348806 with gp120 in Mode II is more stable. The average structure of Mode II was analyzed and compared with the experimental data. The sensitive of C-4 substitution on the azaindole ring may result from its occurence in the vicinity of Trp427. The Large side chain mutations inside the Phe43 cavity, such as S375W and T257R mutation, make steric hindrance for the binding. Other reisdues in the cavity such as Ser256, Thr257, Asn425, Met426 and VAL430 have considerable interactions with the small molecule. The average structure of the complex is consistent with the experimental data of mutation. The binding mode between BMS-378806 and the bounded state gp120 is similar to the binding of Phe43 in CD4 with gp120. The simulation results give an atomic insight to the possible binding mode of this kind of inhibitors.
(2) Inhibitor design targeting to HIV-1 transmembrane protein - gp41
(a) Pharmacophore model construction based on ligands’structures
The software of GASP was used to generate ligand-based pharmacophore models on the basis of the identified structure information of active inhibitors interfering with the six helix bundle formation of gp41. The selected model - Model 01 was comprised of two hydrophobic features, two pairs of hydrogen bond acceptor features and one pair of hydrogen bond donor feature. The mapping of active molecules to the model showed that the hydrophobic features represented the phenyl group or pyrrole group, and the hydrogen bond features represented the hydroxyl group or carboxyl group.
(b) Binding modes research and pharmacophore model construction based on receptor structures
The binding modes of the known inhibitors with the 5-helix gp41 were obtained by using the molecule docking methods. The acceptor-based pharmacophore model was constructed according to the docking results. It is composed of four hydrophobic features, three hydrogen bond acceptor features and one hydrogen bond donor feature.
(c) Pharmacophore model validation
By comparison of the ligand-based pharmacophore model (Model 01), the binding modes of the inhibitors and the acceptor-based pharmacophore model, they all turned out a sort of consistency. The ligand-based pharmacophore model seemed to be a subset of the acceptor-based pharmacophore model, which is necessary for the activity. The filter property of the model was validated by a test database which was composed by molecules randomly selected from the ACDSC database and the known inhibitors. The results show that the model could filter out the active molecules efficiently with an enrichment factor of 5.04.
(d) Virtual screening target to gp41
A virtual screening strategy was designed to combine both the ligand and the receptor structure information. About 2,500,000 molecules from CMC, ACDSC, NCI, MDDR and CHDD were screened. The toxicity and drug-like properties were also estimated. Thirty six molecules were selected finally and two of them were synthesized. Both of the compounds showed the ability to inhibit the infection of the HIV-1 IIIB virus in vitro.
(e) Structural optimization based on NB-2
The de novo drug design method ( LeapFrog ) was used to optimize structure of NB-2 targeting the 5-helix structure of gp41. The docking method was adopted to recalculate the binding modes and the binding free energy of the new compounds. It was found that the binding free energy of new molecules were low than that of NB-2.
The synthesis experiments are undertaken on the way.
(3) Inhibitor design targeting to CCR5
(a) Construction of predicable pharmacophore model
A three dimensional pharmacophore model was developed for a considerable number of pyrrolidine based and butane-based chemokine (C-C motif) receptor 5 (CCR5) antagonists. The most predictive pharmacophore model (Hypo 1), consisting of two positive ionizable points and three hydrophobic groups, had a correlation of 0.924 for the training set, and a cost difference of 63.67 bits between the null cost and the total cost. The model was applied to predict the activity of 74 compounds as a test set with a correlation factor of 0.703. The results indicated that the model was able to provide accurate activity prediction for novel antagonist design. It has been employed to filter a combinatorial database, and the molecules with good predicted activities were selected into the synthesis experiments.
(b) Construction of CoMFA and CoMSIA model
A series of 1,3,4-trisubstituted pyrrolidine-based CCR5 receptor antagonists was taken as our target to construct CoMFA (Comparative Molecular Field Analysis) and CoMSIA (Comparative Molecular Similarity Indices Analysis) models. The training set and test set consisting of 72 and 39 selected molecules, respectively. For the best CoMFA model (CoMFA2), the conventional correlation coefficient r2 = 0.952, the cross-validated coeffient q2 = 0.637, and the correlation factor on the test set prediction R = 0.785, while for the best CoMSIA model (CoMSIA2), r2 = 0.958, q2 = 0.677, and R = 0.806. Furthermore the contour map also provides a visual representation for the contributions of steric, electrostatic, hydrogen-bond and hydrophobic fields. The study could provide useful information for structure optimization of this kind of compounds.
In this paper, a series of research work, including binding mode prediction, pharmacophore model construction and QSAR (Quantitative structure-activity relationship) analysis has been done against the key proteins (gp120, gp41, CCR5) involved in the entry of HIV-1. A binding mode of BMS-378806 with gp120 which is consistent with the experimental data as well as effective pharmacophore models based on gp41 inhibitors and predictable QSAR models based on CCR5 antagonists were achieved. The new compounds targeting to different proteins were designed and a part of them were synthesized and proved to be active. These works may benefit the development of anti-AIDS drug candidates.
引文
1 F. Barre-Sinoussi, J. C. Chermann, F. Rey, M. T. Nugeyre, S. Chamaret, J. Gruest, C. Dauguet, C. Axler-Blin, et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science. 1983, 220(4599): 868~871
2 J. C. Chermann, F. Barre-Sinoussi, C. Dauguet, F. Brun-Vezinet, C. Rouzioux, W. Rozenbaum, and L. Montagnier. Isolation of a new retrovirus in a patient at risk for acquired immunodeficiency syndrome. Antibiotics and Chemotherapy. 1983, 32: 48~53
3 中国卫生部, 2007 年中国艾滋病防治联合评估报告 (2007).
4 D. D. Richman. HIV chemotherapy. Nature. 2001, 410(6831): 995~1001
5 D. Finzi, J. Blankson, J. D. Siliciano, J. B. Margolick, K. Chadwick, T. Pierson, K. Smith, J. Lisziewicz, et al. Latent infection of CD4(+) T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nature Medicine. 1999, 5(5): 512~517
6 曾毅, 陈启民, 耿运琪, 艾滋病毒及其有关病毒, 第一版 (南开大学出版社, 天津, 1999).
7 W. C. Greene. The brightening future of HIV therapeutics. Nature Immunology. 2004, 5(9): 867~871
8 D. Wilkinson. HIV-1: Cofactors provide the entry keys. Current Biology. 1996, 6(9): 1051~1053
9 R. W. Doms. Beyond receptor expression: The influence of receptor conformation, density, and affinity in HIV-1 infection. Virology. 2000, 276(2): 229~237
10 E. A. Berger, P. M. Murphy, and J. M. Farber. CHEMOKINE RECEPTORS AS HIV-1 CORECEPTORS: Roles in Viral Entry, Tropism, and Disease. Annual Review of Immunology. 1999, 17(1): 657~700
11 D. C. Chan, D. Fass, J. M. Berger, and P. S. Kim. Core Structure of gp41 from the HIV Envelope Glycoprotein. Cell. 1997, 89(2): 263~273
12 W. Weissenhorn, A. Dessen, S. C. Harrison, J. J. Skehel, and D. C. Wiley. Atomic structure of the ectodomain from HIV-1 gp41. Nature. 1997, 387(6631): 426~430
13 J. Luban. Absconding with the chaperone: Essential cyclophilin-gag interaction in HIV-1 virions. Cell. 1996, 87(7): 1157~1159
14 J. P. Lalezari, K. Henry, M. O'Hearn, E. Lefebvre, J. Monaner, P. Piliero, S. Walmsley, J. Chung, et al. Enfuvirtide (T-20) in combination with an optimized background (OB) regimen vs. OB alone: Week 24 response among categories of treatment experience and baseline (BL) HIV antiretroviral (ARV) resistance. Abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy. 2002, 42: 266
15 M. H. Shibo Jiang, Z. Qian, and A. K. Debnath. Peptide and Non-peptide HIV Fusion Inhibitors. Current Pharmaceutical Design. 2002, 8(8): 563~580
16 F. E. McCutchan, M. O. Salminen, J. K. Carr, and D. S. Burke. HIV-1 genetic diversity. AIDS. 1996, 10: S13~S20
17 M. Katzman and M. Sudol. Mapping viral DNA specificity to the central region of integrase by using functional human immunodeficiency virus type 1 visna virus chimeric proteins. Journal of Virology. 1998, 72(3): 1744~1753
18 J. M. McCune, L. B. Rabin, M. B. Feinberg, M. Lieberman, J. C. Kosek, G. R. Reyes, and I. L.Weissman. Endoproteolytic Cleavage of Gp160 Is Required for the Activation of Human Immunodeficiency Virus. Cell. 1988, 53(1): 55~67
19 S. M. Hammer. Advances in antiretroviral therapy and viral load monitoring. AIDS. 1996, 10: S1~S11
20 D. D. Ho, A. U. Neumann, A. S. Perelson, W. Chen, J. M. Leonard, and M. Markowitz. Rapid Turnover of Plasma Virions and Cd4 Lymphocytes in Hiv-1 Infection. Nature. 1995, 373(6510): 123~126
21 S. Liu, S. Wu, and S. Jiang. HIV Entry Inhibitors Targeting gp41: From Polypeptides to Small-Molecule Compounds. Current Pharmaceutical Design. 2007, 13(2): 143~162
22 W. L. Jorgensen. The many roles of computation in drug discovery. Science. 2004, 303(5665): 1813~1818
23 H. M. Berman, J. Westbrook, Z. Feng, G. Gilliland, T. N. Bhat, H. Weissig, I. N. Shindyalov, and P. E. Bourne. The Protein Data Bank. Nucleic Acids Research. 2000, 28(1): 235~242
24 陈凯先, 蒋华良, 计算机辅助药物设计-原理、方法及应用, 第一版 (上海科学技术出版社, 上海, 2000).
25 徐筱杰, 侯廷军, 乔学斌, 章威, 计算机辅助药物分子设计, 第一版 (化学工业出版社, 北京, 2004).
26 I. D. Kuntz, J. M. Blaney, S. J. Oatley, R. Langridge, and T. E. Ferrin. A Geometric Approach to Macromolecule-Ligand Interactions. Journal of Molecular Biology. 1982, 161(2): 269~288
27 T. J. A. Ewing and I. D. Kuntz. Critical evaluation of search algorithms for automated molecular docking and database screening. Journal of Computational Chemistry. 1997, 18(9): 1175~1189
28 D. S. Goodsell and A. J. Olson. Automated Docking of Substrates to Proteins by Simulated Annealing. Proteins-Structure Function and Genetics. 1990, 8(3): 195~202
29 G. M. Morris, D. S. Goodsell, R. S. Halliday, R. Huey, W. E. Hart, R. K. Belew, and A. J. Olson. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. Journal of Computational Chemistry. 1998, 19(14): 1639~1662
30 M. Rarey, B. Kramer, T. Lengauer, and G. Klebe. A fast flexible docking method using an incremental construction algorithm. Journal of Molecular Biology. 1996, 261(3): 470~489
31 H. Claussen, C. Buning, M. Rarey, and T. Lengauer. FlexE: Efficient molecular docking considering protein structure variations. Journal of Molecular Biology. 2001, 308(2): 377~395
32 B. A. Luty, Z. R. Wasserman, P. F. W. Stouten, C. N. Hodge, M. Zacharias, and J. A. McCammon. A Molecular Mechanics Grid Method for Evaluation of Ligand-Receptor Interactions. Journal of Computational Chemistry. 1995, 16(4): 454~464
33 C. M. Venkatachalam, X. Jiang, T. Oldfield, and M. Waldman. LigandFit: a novel method for the shape-directed rapid docking of ligands to protein active sites. Journal of Molecular Graphics and Modelling. 2003, 21(4): 289~307
34 Z. Zsoldos, D. Reid, A. Simon, B. S. Sadjad, and A. P. Johnson. eHITS: An innovative approach to the docking and scoring function problems. Current Protein & Peptide Science. 2006, 7(5): 421~435
35 A. N. Jain. Surflex: Fully automatic flexible molecular docking using a molecular similarity-based search engine. Journal of Medicinal Chemistry. 2003, 46(4): 499~511
36 G. Jones, P. Willett, R. C. Glen, A. R. Leach, and R. Taylor. Development and validation of a genetic algorithm for flexible docking. Journal of Molecular Biology. 1997, 267(3): 727~748
37 R. A. Friesner, J. L. Banks, R. B. Murphy, T. A. Halgren, J. J. Klicic, D. T. Mainz, M. P. Repasky,E. H. Knoll, et al. Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. Journal of Medicinal Chemistry. 2004, 47(7): 1739~1749
38 T. A. Halgren, R. B. Murphy, R. A. Friesner, H. S. Beard, L. L. Frye, W. T. Pollard, and J. L. Banks. Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. Journal of Medicinal Chemistry. 2004, 47(7): 1750~1759
39 M. D. Eldridge, C. W. Murray, T. R. Auton, G. V. Paolini, and R. P. Mee. Empirical scoring functions .1. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes. Journal of Computer-Aided Molecular Design. 1997, 11(5): 425~445
40 C. W. Murray, T. R. Auton, and M. D. Eldridge. Empirical scoring functions. 2. The testing of an empirical scoring function for the prediction of ligand-receptor binding affinities and the use of Bayesian regression to improve the quality of the model. Journal of Computer-Aided Molecular Design. 1998, 12(5): 503~519
41 H. J. Bohm. The Development of a Simple Empirical Scoring Function to Estimate the Binding Constant for a Protein Ligand Complex of Known 3-Dimensional Structure. Journal of Computer-Aided Molecular Design. 1994, 8(3): 243~256
42 H. Gohlke, M. Hendlich, and G. Klebe. Knowledge-based scoring function to predict protein-ligand interactions. Journal of Molecular Biology. 2000, 295(2): 337~356
43 I. Muegge and Y. C. Martin. A General and Fast Scoring Function for Protein-Ligand Interactions: A Simplified Potential Approach. Journal of Medicinal Chemistry. 1999, 42(5): 791~804
44 P. S. Charifson, J. J. Corkery, M. A. Murcko, and W. P. Walters. Consensus scoring: A method for obtaining improved hit rates from docking databases of three-dimensional structures into proteins. Journal of Medicinal Chemistry. 1999, 42(25): 5100~5109
45 R. D. Clark, A. Strizhev, J. M. Leonard, J. F. Blake, and J. B. Matthew. Consensus scoring for ligand/protein interactions. Journal of Molecular Graphics & Modelling. 2002, 20(4): 281~295
46 M. Kontoyianni, L. M. McClellan, and G. S. Sokol. Evaluation of docking performance: Comparative data on docking algorithms. Journal of Medicinal Chemistry. 2004, 47(3): 558~565
47 E. Kellenberger, J. Rodrigo, P. Muller, and D. Rognan. Comparative evaluation of eight docking tools for docking and virtual screening accuracy. Proteins-Structure Function and Bioinformatics. 2004, 57(2): 225~242
48 H. A. Carlson. Protein flexibility and drug design: how to hit a moving target. Current Opinion in Chemical Biology. 2002, 6(4): 447~452
49 H. J. Bohm. Ludi - Rule-Based Automatic Design of New Substituents for Enzyme-Inhibitor Leads. Journal of Computer-Aided Molecular Design. 1992, 6(6): 593~606
50 H. J. Bohm. Prediction of binding constants of protein ligands: A fast method for the prioritization of hits obtained from de novo design or 3D database search programs. Journal of Computer-Aided Molecular Design. 1998, 12(4): 309~323
51 P. J. Goodford. A Computational-Procedure for Determining Energetically Favorable Binding-Sites on Biologically Important Macromolecules. Journal of Medicinal Chemistry. 1985, 28(7): 849~857
52 D. N. A. Boobbyer, P. J. Goodford, P. M. McWhinnie, and R. C. Wade. New Hydrogen-Bond Potentials for Use in Determining Energetically Favorable Binding-Sites on Molecules of Known Structure. Journal of Medicinal Chemistry. 1989, 32(5): 1083~1094
53 R. D. Cramer, D. E. Patterson, and J. D. Bunce. Comparative Molecular-Field Analysis(CoMFA) .1. Effect of Shape on Binding of Steroids to Carrier Proteins. Journal of the American Chemical Society. 1988, 110(18): 5959~5967
54 R. D. Cramer, J. D. Bunce, D. E. Patterson, and I. E. Frank. Cross-Validation, Bootstrapping, and Partial Least-Squares Compared with Multiple-Regression in Conventional Qsar Studies. Quantitative Structure-Activity Relationships. 1988, 7(1): 18~25
55 A. Miranker and M. Karplus. Functionality Maps of Binding-Sites - a Multiple Copy Simultaneous Search Method. Proteins: Structure, Function and Genetics. 1991, 11(1): 29~34
56 R. S. Pearlman and K. M. Smith. EA-Inventor: Using VHTS scoring functions for De novo design. Abstracts of Papers of the American Chemical Society. 2004, 228: U365~U365
57 Y. C. Martin, "Distance comparisons: A new strategy for examining three-dimensional structure-activity relationships," in Classical and Three-Dimensional Qsar in Agrochemistry (Amer Chemical Soc, Washington, 1995), pp. 318~329.
58 G. Jones, P. Willett, and R. C. Glen. A genetic algorithm for flexible molecular overlay and pharmacophore elucidation. Journal of Computer-Aided Molecular Design. 1995, 9(6): 532~549
59 Y. Kurogi and O. F. Guner. Pharmacophore modeling and three-dimensional database searching for drug design using catalyst. Current Medicinal Chemistry. 2001, 8(9): 1035~1055
60 A. Smellie. Poling: Promoting Conformational Variation. Journal of Computational Chemistry. 1995, 16: 171~187
61 Y. Patel, V. J. Gillet, G. Bravi, and A. R. Leach. A comparison of the pharmacophore identification programs: Catalyst, DISCO and GASP. Journal of Computer-Aided Molecular Design. 2002, 16(8-9): 653~681
62 C. Charlier, J. P. Henichart, F. Durant, and J. Wouters. Structural insights into human 5-lipoxygenase inhibition: Combined ligand-based and target-based approach. Journal of Medicinal Chemistry. 2006, 49(1): 186~195
63 C. Hansch, R. M. Muir, T. Fujita, P. P. Maloney, F. Geiger, and M. Streich. The Correlation of Biological Activity of Plant Growth Regulators and Chloromycetin Derivatives with Hammett Constants and Partition Coefficients. Journal of the American Chemical Society. 1963, 85(18): 2817~2824
64 S. M. Free and J. W. Wilson. A Mathematical Contribution to Structure-Activity Studies. Journal of Medicinal Chemistry. 1964, 7(4): 395~399
65 L. B. Kier and L. H. Hall. Molecular Connectivity .7. Specific Treatment of Heteroatoms. Journal of Pharmaceutical Sciences. 1976, 65(12): 1806~1809
66 G. M. Crippen. Distance geometry approach to rationalizing binding data. Journal of Medicinal Chemistry. 1979, 22(8): 988~997
67 A. J. Hopfinger. A QSAR investigation of dihydrofolate reductase inhibition by Baker triazines based upon molecular shape analysis. Journal of the American Chemical Society. 1980, 102(24): 7196~7206
68 A. N. Jain, K. Koile, and D. Chapman. Compass: Predicting Biological Activities from Molecular Surface Properties. Performance Comparisons on a Steroid Benchmark. Journal of Medicinal Chemistry. 1994, 37(15): 2315~2327
69 G. Klebe, U. Abraham, and T. Mietzner. Molecular Similarity Indices in a Comparative Analysis (CoMSIA) of Drug Molecules to Correlate and Predict Their Biological Activity. Journal of Medicinal Chemistry. 1994, 37(24): 4130~4146
70 A. Vedani, K. Briem, M. Dobler, H. Dollinger, and D. R. McMasters. Multiple-conformation andprotonation-state representation in 4D-QSAR: The neurokinin-1 receptor system. Journal of Medicinal Chemistry. 2000, 43(23): 4416~4427
71 A. Vedani and M. Dobler. 5D-QSAR: The key for simulating induced fit? Journal of Medicinal Chemistry. 2002, 45(11): 2139~2149
72 A. Vedani, M. Dobler, and M. A. Lill. Combining protein modeling and 6D-QSAR. Simulating the binding of structurally diverse ligands to the estrogen receptor. Journal of Medicinal Chemistry. 2005, 48(11): 3700~3703
73 W. P. Walters, M. T. Stahl, and M. A. Murcko. Virtual screening - an overview. Drug Discovery Today. 1998, 3(4): 160~178
74 A. C. Good, S. R. Krystek, and J. S. Mason. High-throughput and virtual screening: core lead discovery technologies move towards integration. Drug Discovery Today. 2000, 5(12): S61~S69
75 F. Bajorath. Integration of virtual and high-throughput screening. Nature Reviews Drug Discovery. 2002, 1(11): 882~894
76 H. J. Boehm, M. Boehringer, D. Bur, H. Gmuender, W. Huber, W. Klaus, D. Kostrewa, H. Kuehne, et al. Novel inhibitors of DNA gyrase: 3D structure based biased needle screening, hit validation by biophysical methods, and 3D guided optimization. A promising alternative to random screening. Journal of Medicinal Chemistry. 2000, 43(14): 2664~2674
77 T. N. Doman, S. L. McGovern, B. J. Witherbee, T. P. Kasten, R. Kurumbail, W. C. Stallings, D. T. Connolly, and B. K. Shoichet. Molecular docking and high-throughput screening for novel inhibitors of protein tyrosine phosphatase-1B. Journal of Medicinal Chemistry. 2002, 45(11): 2213~2221
78 A. M. Paiva, D. E. Vanderwall, J. S. Blanchard, J. W. Kozarich, J. M. Williamson, and T. M. Kelly. Inhibitors of dihydrodipicolinate reductase, a key enzyme of the diaminopimelate pathway of Mycobacterium tuberculosis. Biochimica Et Biophysica Acta-Protein Structure and Molecular Enzymology. 2001, 1545(1-2): 67~77
79 李洪林, 沈建华, 罗小民, 沈旭, 朱维良, 王希诚, 陈凯先, and 蒋华良. 虚拟筛选与新药发现. 生命科学. 2000, 17(2): 125~131
80 R. F. Service. Molecules get wired. Science. 2001, 294(5551): 2442~2443
81 M. Melnick, S. H. Reich, K. K. Lewis, L. J. Mitchell, D. Nguyen, A. J. Trippe, H. Dawson, J. F. Davies, et al. Bis tertiary amide inhibitors of the HIV-1 protease generated via protein structure-based iterative design. Journal of Medicinal Chemistry. 1996, 39(14): 2795~2811
82 I. J. Enyedy, Y. Ling, K. Nacro, Y. Tomita, X. H. Wu, Y. Y. Cao, R. B. Guo, B. H. Li, et al. Discovery of small-molecule inhibitors of bcl-2 through structure-based computer screening. Journal of Medicinal Chemistry. 2001, 44(25): 4313~4324
83 I. J. Enyedy, S. L. Lee, A. H. Kuo, R. B. Dickson, C. Y. Lin, and S. M. Wang. Structure-based approach for the discovery of bis-benzamidines as novel inhibitors of matriptase. Journal of Medicinal Chemistry. 2001, 44(9): 1349~1355
84 J. Lalezari, M. Thompson, P. Kumar, P. Piliero, R. Davey, T. Murtaugh, K. Patterson, A. Shachoy-Clark, et al. 873140, a novel CCR5 antagonist: antiviral activity and safety during short-term monotherapy in HIV-infected adults. Presented at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Washington, D.C., October 30 through November 2,Abstract H-1137b. 2004
85 M. D. Barratt and R. A. Rodford. The computational prediction of toxicity. Current Opinion in Chemical Biology. 2001, 5(4): 383~388
86 P. D. Kwong, R. Wyatt, J. Robinson, R. W. Sweet, J. Sodroski, and W. A. Hendrickson. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature. 1998, 393(666): 648~659
87 B. Chen, E. M. Vogan, H. Y. Gong, J. J. Skehel, D. C. Wiley, and S. C. Harrison. Structure of an unliganded simian immunodeficiency virus gp120 core. Nature. 2005, 433(7028): 834~841
88 S. T. D. Hsu and A. M. J. J. Bonvin. Atomic insight into the CD4 binding-induced conformational changes in HIV-1 gp120. Proteins-Structure Function and Bioinformatics. 2004, 55(3): 582~593
89 C. D. Rizzuto, R. Wyatt, N. Hernandez-Ramos, Y. Sun, P. D. Kwong, W. A. Hendrickson, and J. Sodroski. A conserved HIV gp120 glycoprotein structure involved in chemokine receptor binding. Science. 1998, 280(5371): 1949~1953
90 T. Schacker, A. C. Collier, R. Coombs, J. D. Unadkat, I. Fox, J. Alam, J. P. Wang, E. Eggert, et al. Phase-I Study of High-Dose, Intravenous Rscd4 in Subjects with Advanced Hiv-1 Infection. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology. 1995, 9(2): 145~152
91 F. M., O'Neill, M. P., B. D.R., P. P., and O. W., "PRO 542 (CD4-IgG2) has a profound impact on HIV-1 replication in the Hu-PBL-SCID mouse model.," presented at the 9th Conference on Retroviruses and Opportunistic Infections, Seattle, Wash, USA, 2002.
92 K. Ikeda, K. Konishi, M. Sato, H. Hoshino, and K. Tanaka. Inhibition of HIV-1 infection by synthetic peptide analogues derived from the NH2-terminal extracellular region of GPR1. Bioorganic & Medicinal Chemistry Letters. 2001, 11(19): 2607~2609
93 M. Ono, Y. Wada, Y. M. Wu, R. Nemori, Y. Jinbo, H. Wang, K. M. Lo, N. Yamaguchi, et al. FP-21399 blocks HIV envelope protein-mediated membrane fusion and concentrates in lymph nodes. Nature Biotechnology. 1997, 15(4): 343~348
94 T. Wang, Z. X. Zhang, O. B. Wallace, M. Deshpande, H. Q. Fang, Z. Yang, L. M. Zadjura, D. L. Tweedie, et al. Discovery of 4-benzoyl-1-[(4-methoxy-1H-pyrrolo[2,3-b]lpyridin-3-yl)oxoacetyl] -2-(R)- methylpiperazine (BMS-378806): A novel HIV-1 attachment inhibitor that interferes with CD4-gp120 interactions. Journal of Medicinal Chemistry. 2003, 46(20): 4236~4239
95 Q. Guo, H. T. Ho, I. Dicker, L. Fan, N. N. Zhou, J. Friborg, T. Wang, B. V. McAuliffe, et al. Biochemical and genetic characterizations of a novel human immunodeficiency virus type 1 inhibitor that blocks gp120-CD4 interactions. Journal of Virology. 2003, 77(19): 10528~10536
96 P. F. Lin, W. Blair, T. Wang, T. Spicer, Q. Guo, N. N. Zhou, Y. F. Gong, H. G. H. Wang, et al. A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding. Proceedings of the National Academy of Sciences of the United States of America. 2003, 100(19): 11013~11018
97 I. Botos, B. R. O'Keefe, S. R. Shenoy, L. K. Cartner, D. M. Ratner, P. H. Seeberger, M. R. Boyd, and A. Wlodawer. Structures of the complexes of a potent anti-HIV protein cyanovirin-N and high mannose oligosaccharides. Journal of Biological Chemistry. 2002, 277(37): 34336~34342
98 J. O. Ojwang, R. W. Buckheit, Y. Pommier, A. Mazumder, K. Devreese, J. A. Este, D. Reymen, L. A. Pallansch, et al. T30177, an Oligonucleotide Stabilized by an Intramolecular Guanosine Octet, Is a Potent Inhibitor of Laboratory Strains and Clinical Isolates of Human- Immunodeficiency -Virus Type-1. Antimicrobial Agents and Chemotherapy. 1995, 39(11): 2426~2435
99 J. A. Este, C. Cabrera, D. Schols, P. Cherepanov, A. Gutierrez, M. Witvrouw, C. Pannecouque, Z. Debyser, et al. Human immunodeficiency virus glycoprotein gp120 as the primary target for the antiviral action of AR177 (Zintevir). Molecular Pharmacology. 1998, 53(2): 340~345
100 E. Lindahl, B. Hess, and D. van der Spoel. GROMACS 3.0: a package for molecular simulation and trajectory analysis. Journal of Molecular Modeling. 2001, 7(8): 306~317
101 X. Daura, A. E. Mark, and W. F. van Gunsteren. Parametrization of aliphatic CHn united atoms of GROMOS96 force field. Journal of Computational Chemistry. 1998, 19(5): 535~547
102 H. J. C. Berendsen, J. P. M. Postma, W. F. van Gunsteren, and J. Hermans, Interaction models for water in relation to protein hydration, Intermolecular Forces (Reidel Publishing Company, 1981), pp. 331~342.
103 H. J. C. Berendsen, J. P. M. Postma, W. F. Vangunsteren, A. Dinola, and J. R. Haak. Molecular-Dynamics with Coupling to an External Bath. Journal of Chemical Physics. 1984, 81(8): 3684~3690
104 B. Hess, H. Bekker, H. J. C. Berendsen, and J. Fraaije. LINCS: A linear constraint solver for molecular simulations. Journal of Computational Chemistry. 1997, 18(12): 1463~1472
105 S. J. Weiner, P. A. Kollman, D. A. Case, U. C. Singh, C. Ghio, G. Alagona, S. Profeta, and P. Weiner. A New Force-Field for Molecular Mechanical Simulation of Nucleic-Acids and Proteins. Journal of the American Chemical Society. 1984, 106(3): 765~784
106 M. Clark, R. D. Cramer, and N. Vanopdenbosch. Validation of the General-Purpose Tripos 5.2 Force-Field. Journal of Computational Chemistry. 1989, 10(8): 982~1012
107 A. W. Schuttelkopf and D. M. F. van Aalten. PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallographica Section D-Biological Crystallography. 2004, 60: 1355~1363
108 N. Madani, A. L. Perdigoto, K. Srinivasan, J. M. Cox, J. J. Chruma, J. LaLonde, M. Head, A. B. Smith, et al. Localized changes in the gp120 envelope glycoprotein confer resistance to human immunodeficiency virus entry inhibitors BMS-806 and #155. Journal of Virology. 2004, 78(7): 3742~3752
109 U. Moebius, L. K. Clayton, S. Abraham, S. C. Harrison, and E. L. Reinherz. The Human Immunodeficiency Virus-Gp120 Binding-Site on Cd4 - Delineation by Quantitative Equilibrium and Kinetic Binding-Studies of Mutants in Conjunction with a High-Resolution Cd4 Atomic-Structure. Journal of Experimental Medicine. 1992, 176(2): 507~517
110 R. W. Sweet, A. Truneh, and W. A. Hendrickson. CD4 - Its Structure, Role in Immune Function and Aids Pathogenesis, and Potential as a Pharmacological Target. Current Opinion in Biotechnology. 1991, 2(4): 622~633
111 J. S. Wang, N. Le, A. Heredia, H. J. Song, R. Redfield, and L. X. Wang. Modification and structure-activity relationship of a small molecule HIV-1 inhibitor targeting the viral envelope glycoprotein gp120. Organic & Biomolecular Chemistry. 2005, 3(9): 1781~1786
112 S. H. Xiang, P. D. Kwong, R. Gupta, C. D. Rizzuto, D. J. Casper, R. Wyatt, L. P. Wang, W. A. Hendrickson, et al. Mutagenic stabilization and/or disruption of a CD4-bound state reveals distinct conformations of the human immunodeficiency virus type 1 gp120 envelope glycoprotein. Journal of Virology. 2002, 76(19): 9888~9899
113 Z. H. Si, N. Madani, J. M. Cox, J. J. Chruma, J. C. Klein, A. Schon, N. Phan, L. Wang, et al. Small-molecule inhibitors of HIV-1 entry block receptor-induced conformational changes in the viral envelope glycoproteins. Proceedings of the National Academy of Sciences of the United States of America. 2004, 101(14): 5036~5041
114 H. J. P. Ryser and R. Fluckiger. Keynote review: Progress in targeting HIV-1 entry. Drug Discovery Today. 2005, 10(16): 1085~1094
115 C. M. Carr and P. S. Kim. A Spring-Loaded Mechanism for the Conformational Change of Influenza Hemagglutinin. Cell. 1993, 73(4): 823~832
116 D. C. Chan and P. S. Kim. HIV Entry and Its Inhibition. Cell. 1998, 93(5): 681~684
117 D. C. Chan, C. T. Chutkowski, and P. S. Kim. Evidence that a prominent cavity in the coiled coil of HIV type 1 gp41 is an attractive drug target. Proceedings of the National Academy of Sciences of the United States of America. 1998, 95(26): 15613~15617
118 L. T. Rimsky, D. C. Shugars, and T. J. Matthews. Determinants of human immunodeficiency virus type 1 resistance to gp41-derived inhibitory peptide. Journal of Virology. 1998, 72(2): 986~993
119 J. Cao, L. Bergeron, E. Helseth, M. Thali, H. Repke, and J. Sodroski. Effects of Amino-Acid Changes in the Extracellular Domain of the Human-Immunodeficiency-Virus Type-1 Gp41 Envelope Glycoprotein. Journal of Virology. 1993, 67(5): 2747~2755
120 H. M. Mo, A. K. Konstantinidis, K. D. Stewart, T. Dekhtyar, T. Ng, K. Swift, E. D. Matayoshi, W. Kati, et al. Conserved residues in the coiled-coil pocket of human immunodeficiency virus type 1 gp41 are essential for viral replication and interhelical interaction. Virology. 2004, 329(2): 319~327
121 M. Lu, M. O. Stoller, S. Wang, J. Liu, M. B. Fagan, and J. H. Nunberg. Structural and Functional Analysis of Interhelical Interactions in the Human Immunodeficiency Virus Type 1 gp41 Envelope Glycoprotein by Alanine-Scanning Mutagenesis. Journal of Virology. 2001, 75(22): 11146~11156
122 H. B. Bernstein, S. P. Tucker, S. R. Kar, S. A. McPherson, D. T. McPherson, J. W. Dubay, J. Lebowitz, R. W. Compans, et al. Oligomerization of the Hydrophobic Heptad Repeat of Gp41. Journal of Virology. 1995, 69(5): 2745~2750
123 P. Poumbourios, K. A. Wilson, R. J. Center, W. ElAhmar, and B. E. Kemp. Human immunodeficiency virus type 1 envelope glycoprotein oligomerization requires the gp41 amphipathic alpha-helical/leucine zipper-like sequence. Journal of Virology. 1997, 71(3): 2041~2049
124 J. M. Kilby, S. Hopkins, T. M. Venetta, B. DiMassimo, G. A. Cloud, J. Y. Lee, L. Alldredge, E. Hunter, et al. Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nature Medicine. 1998, 4(11): 1302~1307
125 V. Oldfield, G. M. Keating, and G. Plosker. Enfuvirtide - A review of its use in the management of HIV infection. Drugs. 2005, 65(8): 1139~1160
126 J. M. Kilby, J. P. Lalezari, J. J. Eron, M. Carlson, C. Cohen, R. C. Arduino, J. C. Goodgame, J. E. Gallant, et al. The safety, plasma pharmacokinetics, and antiviral activity of subcutaneous enfuvirtide (T-20), a peptide inhibitor of gp41-mediated virus fusion, in HIV-infected adults. Aids Research and Human Retroviruses. 2002, 18(10): 685~693
127 C. Wild, T. Oas, C. McDanal, D. Bolognesi, and T. Matthews. A Synthetic Peptide Inhibitor of Human-Immunodeficiency-Virus Replication - Correlation between Solution Structure and Viral Inhibition. Proceedings of the National Academy of Sciences of the United States of America. 1992, 89(21): 10537~10541
128 S. B. Jiang, K. Lin, N. Strick, and A. R. Neurath. HIV-1 Inhibition by a Peptide. Nature. 1993, 365(6442): 113
129 C. T. Wild, D. C. Shugars, T. K. Greenwell, C. B. McDanal, and T. J. Matthews. Peptides Corresponding to a Predictive Alpha-Helical Domain of Human-Immunodeficiency-Virus Type-1Gp41 Are Potent Inhibitors of Virus-Infection. Proceedings of the National Academy of Sciences of the United States of America. 1994, 91(21): 9770~9774
130 M. Lu, S. C. Blacklow, and P. S. Kim. A Trimeric Structural Domain of the HIV-1 Transmembrane Glycoprotein. Nature Structural Biology. 1995, 2(12): 1075~1082
131 M. Lu and P. S. Kim. A trimeric structural subdomain of the HIV-1 transmembrane glycoprotein. Journal of Biomolecular Structure & Dynamics. 1997, 15(3): 465~471
132 X. P. Zhang, K. Nieforth, J. M. Lang, R. Rouzier-Panis, J. Reynes, A. Dorr, S. Kolis, M. R. Stiles, et al. Pharmacokinetics of plasma enfuvirtide after subcutaneous administration to patients with human immunodeficiency virus: Inverse Gaussian density absorption and 2-compartment disposition. Clinical Pharmacology & Therapeutics. 2002, 72(1): 10~19
133 J. J. Eron, R. M. Gulick, J. A. Bartlett, T. Merigan, R. Arduino, J. M. Kilby, B. Yangco, A. Diers, et al. Short-term safety and antiretroviral activity of T-1249, a second-generation fusion inhibitor of HIV. Journal of Infectious Diseases. 2004, 189(6): 1075~1083
134 L. Martin-Carbonero. Discontinuation of the clinical development of fusion inhibitor T-1249. Aids Reviews. 2004, 6(1): 61
135 D. M. Eckert, V. N. Malashkevich, L. H. Hong, P. A. Carr, and P. S. Kim. Inhibiting HIV-1 Entry: Discovery of D-Peptide Inhibitors that Target the gp41 Coiled-Coil Pocket. Cell. 1999, 99(1): 103~115
136 A. Otaka, M. Nakamura, D. Nameki, E. Kodama, S. Uchiyama, S. Nakamura, H. Nakano, H. Tamamura, et al. Remodeling of gp41-C34 peptide leads to highly effective inhibitors of the fusion of HIV-1 with target cells. Angewandte Chemie-International Edition. 2002, 41(16): 2938~2940
137 J. K. Judice, J. Y. K. Tom, W. Huang, T. Wrin, J. Vennari, C. J. Petropoulos, and R. S. McDowell. Inhibition of HIV type 1 infectivity by constrained alpha-helical peptides: Implications for the viral fusion mechanism. Proceedings of the National Academy of Sciences of the United States of America. 1997, 94(25): 13426~13430
138 S. K. Sia, P. A. Carr, A. G. Cochran, V. N. Malashkevich, and P. S. Kim. Short constrained peptides that inhibit HIV-1 entry. Proceedings of the National Academy of Sciences of the United States of America. 2002, 99(23): 14664~14669
139 D. M. Eckert and P. S. Kim. Design of potent inhibitors of HIV-1 entry from the gp41 N-peptide region. Proceedings of the National Academy of Sciences of the United States of America. 2001, 98(20): 11187~11192
140 C. A. Bewley, J. M. Louis, R. Ghirlando, and G. M. Clore. Design of a novel peptide inhibitor of HIV fusion that disrupts the internal trimeric coiled-coil of gp41. Journal of Biological Chemistry. 2002, 277(16): 14238~14245
141 M. J. Root, M. S. Kay, and P. S. Kim. Protein design of an HIV-1 entry inhibitor. Science. 2001, 291(5505): 884~888
142 M. J. Root and H. K. Steger. HIV-1 gp41 as a target for viral entry inhibition. Current Pharmaceutical Design. 2004, 10(15): 1805~1825
143 M. J. Root and D. H. Hamer. Targeting therapeutics to an exposed and conserved binding element of the HIV-1 fusion protein. Proceedings of the National Academy of Sciences of the United States of America. 2003, 100(9): 5016~5021
144 L. Ni, G. F. Gao, and P. Tien. Rational design of highly potent HIV-1 fusion inhibitory proteins: Implication for developing antiviral therapeutics. Biochemical and Biophysical ResearchCommunications. 2005, 332(3): 831~836
145 R. M. Markosyan, X. W. Maj, F. S. Cohen, and G. B. Melikyan. The mechanism of inhibition of HIV-1 env-mediated cell-cell fusion by recombinant cores of gp41 ectodomain. Virology. 2002, 302(1): 174~184
146 J. M. Louis, C. A. Bewley, and G. M. Clore. Design and properties of N-CCG-gp41, a chimeric gp41 molecule with nanomolar HIV fusion inhibitory activity. Journal of Biological Chemistry. 2001, 276(31): 29485~29489
147 H. Ji, W. Shu, F. T. Burling, S. B. Jiang, and M. Lu. Inhibition of human immunodeficiency virus type 1 infectivity by the gp41 core: Role of a conserved hydrophobic cavity in membrane fusion. Journal of Virology. 1999, 73(10): 8578~8586
148 S. B. Jiang, K. Lin, L. Zhang, and A. K. Debnath. A screening assay for antiviral compounds targeted to the HIV-1 gp41 core structure using a conformation-specific monoclonal antibody. Journal of Virological Methods. 1999, 80(1): 85~96
149 S. Jiang, K. Lin, and M. Lu. A conformation-specific monoclonal antibody reacting with fusion-active gp41 from the human immunodeficiency virus type 1 envelope glycoprotein. Journal of Virology. 1998, 72(12): 10213~10217
150 S. W. Liu, L. Boyer-Chatenet, H. Lu, and S. B. Jiang. Rapid and automated fluorescence-linked immunosorbent assay for high-throughput screening of HIV-1 fusion inhibitors targeting gp41. Journal of Biomolecular Screening. 2003, 8(6): 685~693
151 L. A. Hong, Q. Zhao, Z. K. Xu, and S. B. Jiang. Automatic quantitation of HIV-1 mediated cell-to-cell fusion with a digital image analysis system (DIAS): application for rapid screening of HIV-1 fusion inhibitors. Journal of Virological Methods. 2003, 107(2): 155~161
152 A. K. Debnath, L. Radigan, and S. Jiang. Structure-Based Identification of Small Molecule Antiviral Compounds Targeted to the gp41 Core Structure of the Human Immunodeficiency Virus Type 1. Journal of Medicinal Chemistry 1999, 42(17): 3203~3209
153 K. P. Naicker, S. B. Jiang, H. Lu, J. H. Ni, L. Boyer-Chatenet, L. X. Wang, and A. K. Debnath. Synthesis and anti-HIV-1 activity of 4-[4-(4,6-bisphenylamino-[1,3,5]triazin-2-ylamino)-5- methoxy-2-methylphe nylazo]-5-hydroxynaphthalene-2,7-disulfonic acid and its derivatives. Bioorganic and Medicinal Chemistry. 2004, 12(5): 1215~1220
154 Q. Zhao, J. T. Ernst, A. D. Hamilton, A. K. Debnath, and S. B. Jiang. XTT formazan widely used to detect cell viability inhibits HIV type 1 infection in vitro by targeting gp41. Aids Research and Human Retroviruses. 2002, 18(14): 989~997
155 S. B. Jiang, H. Lu, S. W. Liu, Q. Zhao, Y. X. He, and A. K. Debnath. N-substituted pyrrole derivatives as novel human immunodeficiency virus type 1 entry inhibitors that interfere with the gp41 six-helix bundle formation and block virus fusion. Antimicrobial Agents and Chemotherapy. 2004, 48(11): 4349~4359
156 J. T. Ernst, O. Kutzki, A. K. Debnath, S. Jiang, H. Lu, and A. D. Hamilton. Design of a protein surface antagonist based on alpha-helix mimicry: Inhibition of gp41 assembly and viral fusion. Angewandte Chemie-International Edition. 2002, 41(2): 278~281
157 Y. Xu, H. Lu, J. P. Kennedy, X. X. Yan, L. A. McAllister, N. Yamamoto, J. A. Moss, G. E. Boldt, et al. Evaluation of "credit card" libraries for inhibition of HIV-1 gp41 fusogenic core formation. Journal of Combinatorial Chemistry. 2006, 8(4): 531~539
158 S. W. Liu, H. Lu, Q. Zhao, Y. X. He, J. K. Niu, A. K. Debnath, S. G. Wu, and S. B. Jiang. Theaflavin derivatives in black tea and catechin derivatives in green tea inhibit HIV-1 entry bytargeting gp41. Biochimica Et Biophysica Acta-General Subjects. 2005, 1723(1-3): 270~281
159 S. Lee-Huang, P. L. Huang, D. Zhang, J. W. Lee, J. Bao, Y. Sun, Y.-T. Chang, J. Zhang, et al. Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol: Part I. Integrase inhibition. Biochemical and Biophysical Research Communications. 2007, 354(4): 872~878
160 J. Bao, D. W. Zhang, J. Z. H. Zhang, P. L. Huang, P. L. Huang, and S. Lee-Huang. Computational study of bindings of olive leaf extract (OLE) to HIV-1 fusion protein gp41. FEBS Letters. 2007, 581(14): 2737~2742
161 R. X. Wang, Y. Gao, and L. H. Lai. LigBuilder: A multi-purpose program for structure-based drug design. Journal of Molecular Modeling. 2000, 6(7-8): 498~516
162 A. C. Wallace, R. A. Laskowski, and J. M. Thornton. Ligplot - a Program to Generate Schematic Diagrams of Protein Ligand Interactions. Protein Engineering. 1995, 8(2): 127~134
163 C. Bissantz, G. Folkers, and D. Rognan. Protein-based virtual screening of chemical databases. 1. Evaluation of different docking/scoring combinations. Journal of Medicinal Chemistry. 2000, 43(25): 4759~4767
164 M. A. Miteva, W. H. Lee, M. O. Montes, and B. O. Villoutreix. Fast Structure-Based Virtual Ligand Screening Combining FRED, DOCK, and Surflex. Journal of Medicinal Chemistry. 2005, 48(19): 6012~6022
165 R. G. Gould and W. A. Jacobs. The Synthesis of Certain Substituted Quinolines and
5,6-Benzoquinolines. Journal of the American Chemical Society. 1939, 61(10): 2890~2895
166 Y. F. Suen, L. Robins, B. X. Yang, A. S. Verkman, M. H. Nantz, and M. J. Kurth. Sulfamoyl-4-oxoquinoline-3-carboxamides: Novel potentiators of defective Delta F508-cystic fibrosis transmembrane conductance regulator chloride channel gating. Bioorganic & Medicinal Chemistry Letters. 2006, 16(3): 537~540
167 D. Farcasiu, J. Jahme, and C. Ruchardt. Relative Reactivity of Bridgehead Adamantyl and Homoadamantyl Substrates from Solvolyses with Heptafluorobutyrate as a Highly Reactive Carboxylate Leaving Group - Absence of Sn2 Character of Solvolysis of Tert-Butyl Derivatives. Journal of the American Chemical Society. 1985, 107(20): 5717~5722
168 K. Kettler, J. Sakowski, J. Wiesner, R. Ortmann, H. Jomaa, and M. Schlitzer. Novel lead structures for antimalarial farnesyltransferase inhibitors. Pharmazie. 2005, 60(5): 323~327
169 C. G. Dave and H. A. Joshipura. Microwave assisted Gould-Jacob reaction: Synthesis of 4-quinolones under solvent free conditions. Indian Journal of Chemistry Section B-Organic Chemistry Including Medicinal Chemistry. 2002, 41(3): 650~652
170 H. K. Deng, R. Liu, W. Ellmeier, S. Choe, D. Unutmaz, M. Burkhart, P. DiMarzio, S. Marmon, et al. Identification of a major co-receptor for primary isolates of HIV-1. Nature. 1996, 381(6584): 661~666
171 L. J. Wu, N. P. Gerard, R. Wyatt, H. Choe, C. Parolin, N. Ruffing, A. Borsetti, A. A. Cardoso, et al. CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5. Nature. 1996, 384(6605): 179~183
172 R. Jahn, T. Lang, and T. C. Sudhof. Membrane fusion. Cell. 2003, 112(4): 519~533
173 M. Samson, F. Libert, B. J. Doranz, J. Rucker, C. Liesnard, C. M. Farber, S. Saragosti, C. Lapoumeroulie, et al. Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature. 1996, 382(6593): 722~725
174 S. G. Mills and J. A. DeMartino. Chemokine receptor-directed agents as novel anti-HIV-1therapies. Current topics in Medicinal Chemistry. 2004, 4: 1017~1034
175 K. Maeda, H. Nakata, H. Ogata, Y. Koh, T. Miyakawa, and H. Mitsuya. The current status of, and challenges in, the development of CCR5 inhibitors as therapeutics for HIV-1 infection. Current Opinion in Pharmacology. 2004, 4(5): 447~452
176 M. Baba, O. Nishimura, N. Kanzaki, M. Okamoto, H. Sawada, Y. Iizawa, M. Shiraishi, Y. Aramaki, et al. A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proceedings of the National Academy of Sciences of the United States of America. 1999, 96(10): 5698~5703
177 M. Shiraishi, Y. Aramaki, M. Seto, H. Imoto, Y. Nishikawa, N. Kanzaki, M. Okamoto, H. Sawada, et al. Discovery of novel, potent, and selective small-molecule CCR5 antagonists as anti-HIV-1 agents: Synthesis and biological evaluation of anilide derivatives with a quaternary ammonium moiety. Journal of Medicinal Chemistry. 2000, 43(10): 2049~2063
178 J. M. Strizki, S. Xu, N. E. Wagner, L. Wojcik, J. Liu, Y. Hou, M. Endres, A. Palani, et al. SCH-C (SCH 351125), an orally bioavailable, small molecule antagonist of the chemokine receptor CCR5, is a potent inhibitor of HIV-1 infection in vitro and in vivo. Proceedings of the National Academy of Sciences of the United States of America. 2001, 98(22): 12718~12723
179 J. R. Tagat, S. W. McCombie, D. Nazareno, M. A. Labroli, Y. S. Xiao, R. W. Steensma, J. M. Strizki, B. M. Baroudy, et al. Piperazine-based CCR5 antagonists as HIV-1 inhibitors. IV. Discovery of 1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]-4-[4-{2-methoxy-1(R)-4-(trifluoromethyl) -phenyl}ethyl-3(S)-methyl-1-piperazinyl]-4-methylpiperidine (Sch-417690/Sch-D), a potent, highly selective, and orally bioavailable CCR5 antagonist. Journal of Medicinal Chemistry. 2004, 47(10): 2405~2408
180 A. L. Pozniak, G. Fatkenheuer, M. Johnson, I. M. Hoepelman, J. Rockstroh, F. Goebel, S. Abel, I. James, et al., "Effect of short-term monotherapy with UK-427,857 on viral load in HIV-infected patients," (Chicago, 2003).
181 W. Kazmierski, N. Bifulco, H. B. Yang, L. Boone, F. DeAnda, C. Watson, and T. Kenakin. Recent progress in discovery of small-molecule CCR5 chemokine receptor ligands as HIV-1 inhibitors. Bioorganic and Medicinal Chemistry. 2003, 11(13): 2663~2676
182 K. Maeda, K. Yoshimura, S. Shibayama, H. Habashita, H. Tada, K. Sagwa, T. Miyakawa, M. Aoki, et al. Novel low molecular weight spirodiketopiperazine derivatives potently inhibit R5 HIV-1 infection through their antagonistic effects on CCR5. Journal of Biological Chemistry. 2001, 276: 35194~35200
183 K. Maeda, H. Nakata, Y. Koh, T. Miyakawa, H. Ogata, Y. Takaoka, S. Shibayama, K. Sagawa, et al. Spirodiketopiperazine-based CCR5 inhibitor which preserves CC-Chemokine/CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus type 1 in vitro. Journal of Virology. 2004, 78(16): 8654~8662
184 K. Shankaran, K. L. Donnelly, S. K. Shah, C. G. Caldwell, P. Chen, P. E. Finke, B. Oates, M. MacCoss, et al. Syntheses and biological evaluation of 5-(piperidin-1-yl)-3-phenyl-pentylsulfones as CCR5 antagonists. Bioorganic and Medicinal Chemistry Letters. 2004, 14(13): 3589~3593
185 M. Shu, J. L. Loebach, K. A. Parker, S. G. Mills, K. T. Chapman, D.-M. Shen, L. Malkowitz, M. S. Springer, et al. Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 3: SAR studies on the benzylpyrazole segment. Bioorganic and Medicinal Chemistry Letters. 2004, 14(4): 947~952
186 C. P. Dorn, P. E. Finke, B. Oates, R. J. Budhu, S. G. Mills, M. MacCoss, L. Malkowitz, M. S.Springer, et al. Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 1: Discovery and initial structure–activity relationships for 1-amino-2-phenyl-4-(piperidin-1-yl)butanes. Bioorganic and Medicinal Chemistry Letters. 2001, 11(2): 259~264
187 P. E. Finke, L. C. Meurer, B. Oates, S. G. Mills, M. MacCoss, L. Malkowitz, M. S. Springer, B. L. Daugherty, et al. Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 2: structure–activity relationships for substituted 2-aryl-1-[N-(methyl)-N-(phenylsulfonyl)amino] -4-(piperidin-1-yl)butanes. Bioorganic and Medicinal Chemistry Letters. 2001, 11(2): 265~270
188 P. E. Finke, L. C. Meurer, B. Oates, S. K. Shah, J. L. Loebach, S. G. Mills, M. MacCoss, L. Castonguay, et al. Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 3: A proposed pharmacophore model for 1-[N-(methyl)-N-(phenylsulfonyl)amino]-2-(phenyl)-4-[4- (substituted)piperidin-1-yl]butanes. Bioorganic and Medicinal Chemistry Letters. 2001, 11(18): 2469~2473
189 P. E. Finke, B. Oates, S. G. Mills, M. MacCoss, L. Malkowitz, M. S. Springer, S. L. Gould, J. A. DeMartino, et al. Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 4: synthesis and structure–Activity relationships for 1-[N-(Methyl)-N-(phenylsulfonyl)amino]-2-(phenyl)-4- (4-(N-(alkyl)-N-(benzyloxycarbonyl)amino)piperidin-1-yl)butanes. Bioorganic and Medicinal Chemistry Letters. 2001, 11(18): 2475~2479
190 C. L. Lynch, A. L. Gentry, J. J. Hale, S. G. Mills, M. MacCoss, L. Malkowitz, M. S. Springer, S. L. Gould, et al. CCR5 antagonists: bicyclic isoxazolidines as conformationally constrained N-1-substituted pyrrolidines. Bioorganic and Medicinal Chemistry Letters. 2002, 12(4): 677~679
191 C. A. Willoughby, S. C. Berk, K. G. Rosauer, S. Degrado, K. T. Chapman, S. L. Gould, M. S. Springer, L. Malkowitz, et al. Combinatorial synthesis of CCR5 antagonists. Bioorganic and Medicinal Chemistry Letters. 2001, 11(24): 3137~3141
192 D. Kim, L. Wang, C. G. Caldwell, P. Chen, P. E. Finke, B. Oates, M. MacCoss, S. G. Mills, et al. Design, synthesis, and SAR of heterocycle-containing antagonists of the human CCR5 receptor for the treatment of HIV-1 infection. Bioorganic and Medicinal Chemistry Letters. 2001, 11(24): 3103~3106
193 D. Kim, L. Wang, C. G. Caldwell, P. Chen, P. E. Finke, B. Oates, M. MacCoss, S. G. Mills, et al. Discovery of human CCR5 antagonists containing hydantoins for the treatment of HIV-1 infection. Bioorganic and Medicinal Chemistry Letters. 2001, 11(24): 3099~3102
194 J. N. Burrows, J. G. Cumming, S. M. Fillery, G. A. Hamlin, J. A. Hudson, R. J. Jackson, S. McLaughlin, and J. S. Shaw. Modulators of the human CCR5 receptor. Part 1: Discovery and initial SAR of 1-(3,3-diphenylpropyl)-piperidinyl amides and ureas. Bioorganic and Medicinal Chemistry Letters. 2005, 15(1): 25~28
195 J. G. Cumming, S. J. Brown, A. E. Cooper, A. W. Faull, A. P. Flynn, K. Grime, J. Oldfield, J. S. Shaw, et al. Modulators of the human CCR5 receptor. Part 3: SAR of substituted 1-[3-(4- methanesulfonylphenyl)-3-phenylpropyl]-piperidinyl phenylacetamides. Bioorganic & Medicinal Chemistry Letters. 2006, 16(13): 3533~3536
196 D. A Kim, L. Wang, J. J. Hale, C. L. Lynch, R. J. Budhu, M. MacCoss, S. G. Mills, L. Malkowitz, et al. Potent 1,3,4-trisubstituted pyrrolidine CCR5 receptor antagonists: effects of fused heterocycles on antiviral activity and pharmacokinetic properties. Bioorganic and Medicinal Chemistry Letters. 2005, 15(8): 2129~2134
197 C. A. Willoughby, K. G. Rosauer, J. J. Hale, R. J. Budhu, S. G. Mills, K. T. Chapman, M. MacCoss, L. Malkowitz, et al. 1,3,4 trisubstituted pyrrolidine CCR5 receptor antagonists bearing 4-aminoheterocycle substituted piperidine side chains. Bioorganic and Medicinal Chemistry Letters. 2003, 13(3): 427~431
198 J. J. Hale, R. J. Budhu, S. G. Mills, M. MacCoss, L. Malkowitz, S. Siciliano, S. L. Gould, J. A. DeMartino, et al. 1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 1: discovery of the pyrrolidine scaffold and determination of its stereochemical requirements. Bioorganic and Medicinal Chemistry Letters. 2001, 11(11): 1437~1440
199 J. J. Hale, R. J. Budhu, E. B. Holson, P. E. Finke, B. Oates, S. G. Mills, M. MacCoss, S. L. Gould, et al. 1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 2: lead optimization affording selective, orally bioavailable compounds with potent Anti-HIV activity. Bioorganic and Medicinal Chemistry Letters. 2001, 11(20): 2741~2745
200 J. J. Hale, R. J. Budhu, S. G. Mills, M. MacCoss, S. L. Gould, J. A. DeMartino, M. S. Springer, S. J. Siciliano, et al. 1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 3: polar functionality and its effect on anti-HIV-1 activity. Bioorganic and Medicinal Chemistry Letters. 2002, 12(20): 2997~3000
201 C. L. Lynch, J. J. Hale, R. J. Budhu, A. L. Gentry, S. G. Mills, K. T. Chapman, M. MacCoss, L. Malkowitz, et al. 1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 4: Synthesis of N-1 acidic functionality affording analogues with enhanced antiviral activity against HIV. Bioorganic and Medicinal Chemistry Letters. 2002, 12(20): 3001~3004
202 S. J. Siciliano, S. E. Kuhmann, Y. Weng, N. Madani, M. S. Springer, J. E. Lineberger, R. Danzeisen, M. D. Miller, et al. A critical site in the core of the CCR5 chemokine receptor required for binding and infectivity of human immunodeficiency virus type 1. Journal of Biological Chemistry. 1999, 274: 1905~1913
203 O. F. Güner, Pharmacophore Perception, Development and Use in Drug Design (International University Line:La Jolla, CA, 1999).
204 Y. Xu, H. Liu, C. Y. Niu, C. Luo, X. M. Luo, J. H. Shen, K. X. Chen, and H. L. Jiang. Molecular docking and 3D QSAR studies on 1-amino-2-phenyl-4-(piperidin-1-yl)-butanes based on the structural modeling of human CCR5 receptor. Bioorganic and Medicinal Chemistry. 2004, 12(23): 6193~6208
205 M. S. Song, C. M. Breneman, and N. Sukumar. Three-dimensional quantitative structure-activity relationship analyses of piperidine-based CCR5 receptor antagonists. Bioorganic and Medicinal Chemistry. 2004, 12(2): 489~499
2 J. C. Chermann, F. Barre-Sinoussi, C. Dauguet, F. Brun-Vezinet, C. Rouzioux, W. Rozenbaum, and L. Montagnier. Isolation of a new retrovirus in a patient at risk for acquired immunodeficiency syndrome. Antibiotics and Chemotherapy. 1983, 32: 48~53
3 中国卫生部, 2007 年中国艾滋病防治联合评估报告 (2007).
4 D. D. Richman. HIV chemotherapy. Nature. 2001, 410(6831): 995~1001
5 D. Finzi, J. Blankson, J. D. Siliciano, J. B. Margolick, K. Chadwick, T. Pierson, K. Smith, J. Lisziewicz, et al. Latent infection of CD4(+) T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nature Medicine. 1999, 5(5): 512~517
6 曾毅, 陈启民, 耿运琪, 艾滋病毒及其有关病毒, 第一版 (南开大学出版社, 天津, 1999).
7 W. C. Greene. The brightening future of HIV therapeutics. Nature Immunology. 2004, 5(9): 867~871
8 D. Wilkinson. HIV-1: Cofactors provide the entry keys. Current Biology. 1996, 6(9): 1051~1053
9 R. W. Doms. Beyond receptor expression: The influence of receptor conformation, density, and affinity in HIV-1 infection. Virology. 2000, 276(2): 229~237
10 E. A. Berger, P. M. Murphy, and J. M. Farber. CHEMOKINE RECEPTORS AS HIV-1 CORECEPTORS: Roles in Viral Entry, Tropism, and Disease. Annual Review of Immunology. 1999, 17(1): 657~700
11 D. C. Chan, D. Fass, J. M. Berger, and P. S. Kim. Core Structure of gp41 from the HIV Envelope Glycoprotein. Cell. 1997, 89(2): 263~273
12 W. Weissenhorn, A. Dessen, S. C. Harrison, J. J. Skehel, and D. C. Wiley. Atomic structure of the ectodomain from HIV-1 gp41. Nature. 1997, 387(6631): 426~430
13 J. Luban. Absconding with the chaperone: Essential cyclophilin-gag interaction in HIV-1 virions. Cell. 1996, 87(7): 1157~1159
14 J. P. Lalezari, K. Henry, M. O'Hearn, E. Lefebvre, J. Monaner, P. Piliero, S. Walmsley, J. Chung, et al. Enfuvirtide (T-20) in combination with an optimized background (OB) regimen vs. OB alone: Week 24 response among categories of treatment experience and baseline (BL) HIV antiretroviral (ARV) resistance. Abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy. 2002, 42: 266
15 M. H. Shibo Jiang, Z. Qian, and A. K. Debnath. Peptide and Non-peptide HIV Fusion Inhibitors. Current Pharmaceutical Design. 2002, 8(8): 563~580
16 F. E. McCutchan, M. O. Salminen, J. K. Carr, and D. S. Burke. HIV-1 genetic diversity. AIDS. 1996, 10: S13~S20
17 M. Katzman and M. Sudol. Mapping viral DNA specificity to the central region of integrase by using functional human immunodeficiency virus type 1 visna virus chimeric proteins. Journal of Virology. 1998, 72(3): 1744~1753
18 J. M. McCune, L. B. Rabin, M. B. Feinberg, M. Lieberman, J. C. Kosek, G. R. Reyes, and I. L.Weissman. Endoproteolytic Cleavage of Gp160 Is Required for the Activation of Human Immunodeficiency Virus. Cell. 1988, 53(1): 55~67
19 S. M. Hammer. Advances in antiretroviral therapy and viral load monitoring. AIDS. 1996, 10: S1~S11
20 D. D. Ho, A. U. Neumann, A. S. Perelson, W. Chen, J. M. Leonard, and M. Markowitz. Rapid Turnover of Plasma Virions and Cd4 Lymphocytes in Hiv-1 Infection. Nature. 1995, 373(6510): 123~126
21 S. Liu, S. Wu, and S. Jiang. HIV Entry Inhibitors Targeting gp41: From Polypeptides to Small-Molecule Compounds. Current Pharmaceutical Design. 2007, 13(2): 143~162
22 W. L. Jorgensen. The many roles of computation in drug discovery. Science. 2004, 303(5665): 1813~1818
23 H. M. Berman, J. Westbrook, Z. Feng, G. Gilliland, T. N. Bhat, H. Weissig, I. N. Shindyalov, and P. E. Bourne. The Protein Data Bank. Nucleic Acids Research. 2000, 28(1): 235~242
24 陈凯先, 蒋华良, 计算机辅助药物设计-原理、方法及应用, 第一版 (上海科学技术出版社, 上海, 2000).
25 徐筱杰, 侯廷军, 乔学斌, 章威, 计算机辅助药物分子设计, 第一版 (化学工业出版社, 北京, 2004).
26 I. D. Kuntz, J. M. Blaney, S. J. Oatley, R. Langridge, and T. E. Ferrin. A Geometric Approach to Macromolecule-Ligand Interactions. Journal of Molecular Biology. 1982, 161(2): 269~288
27 T. J. A. Ewing and I. D. Kuntz. Critical evaluation of search algorithms for automated molecular docking and database screening. Journal of Computational Chemistry. 1997, 18(9): 1175~1189
28 D. S. Goodsell and A. J. Olson. Automated Docking of Substrates to Proteins by Simulated Annealing. Proteins-Structure Function and Genetics. 1990, 8(3): 195~202
29 G. M. Morris, D. S. Goodsell, R. S. Halliday, R. Huey, W. E. Hart, R. K. Belew, and A. J. Olson. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. Journal of Computational Chemistry. 1998, 19(14): 1639~1662
30 M. Rarey, B. Kramer, T. Lengauer, and G. Klebe. A fast flexible docking method using an incremental construction algorithm. Journal of Molecular Biology. 1996, 261(3): 470~489
31 H. Claussen, C. Buning, M. Rarey, and T. Lengauer. FlexE: Efficient molecular docking considering protein structure variations. Journal of Molecular Biology. 2001, 308(2): 377~395
32 B. A. Luty, Z. R. Wasserman, P. F. W. Stouten, C. N. Hodge, M. Zacharias, and J. A. McCammon. A Molecular Mechanics Grid Method for Evaluation of Ligand-Receptor Interactions. Journal of Computational Chemistry. 1995, 16(4): 454~464
33 C. M. Venkatachalam, X. Jiang, T. Oldfield, and M. Waldman. LigandFit: a novel method for the shape-directed rapid docking of ligands to protein active sites. Journal of Molecular Graphics and Modelling. 2003, 21(4): 289~307
34 Z. Zsoldos, D. Reid, A. Simon, B. S. Sadjad, and A. P. Johnson. eHITS: An innovative approach to the docking and scoring function problems. Current Protein & Peptide Science. 2006, 7(5): 421~435
35 A. N. Jain. Surflex: Fully automatic flexible molecular docking using a molecular similarity-based search engine. Journal of Medicinal Chemistry. 2003, 46(4): 499~511
36 G. Jones, P. Willett, R. C. Glen, A. R. Leach, and R. Taylor. Development and validation of a genetic algorithm for flexible docking. Journal of Molecular Biology. 1997, 267(3): 727~748
37 R. A. Friesner, J. L. Banks, R. B. Murphy, T. A. Halgren, J. J. Klicic, D. T. Mainz, M. P. Repasky,E. H. Knoll, et al. Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. Journal of Medicinal Chemistry. 2004, 47(7): 1739~1749
38 T. A. Halgren, R. B. Murphy, R. A. Friesner, H. S. Beard, L. L. Frye, W. T. Pollard, and J. L. Banks. Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. Journal of Medicinal Chemistry. 2004, 47(7): 1750~1759
39 M. D. Eldridge, C. W. Murray, T. R. Auton, G. V. Paolini, and R. P. Mee. Empirical scoring functions .1. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes. Journal of Computer-Aided Molecular Design. 1997, 11(5): 425~445
40 C. W. Murray, T. R. Auton, and M. D. Eldridge. Empirical scoring functions. 2. The testing of an empirical scoring function for the prediction of ligand-receptor binding affinities and the use of Bayesian regression to improve the quality of the model. Journal of Computer-Aided Molecular Design. 1998, 12(5): 503~519
41 H. J. Bohm. The Development of a Simple Empirical Scoring Function to Estimate the Binding Constant for a Protein Ligand Complex of Known 3-Dimensional Structure. Journal of Computer-Aided Molecular Design. 1994, 8(3): 243~256
42 H. Gohlke, M. Hendlich, and G. Klebe. Knowledge-based scoring function to predict protein-ligand interactions. Journal of Molecular Biology. 2000, 295(2): 337~356
43 I. Muegge and Y. C. Martin. A General and Fast Scoring Function for Protein-Ligand Interactions: A Simplified Potential Approach. Journal of Medicinal Chemistry. 1999, 42(5): 791~804
44 P. S. Charifson, J. J. Corkery, M. A. Murcko, and W. P. Walters. Consensus scoring: A method for obtaining improved hit rates from docking databases of three-dimensional structures into proteins. Journal of Medicinal Chemistry. 1999, 42(25): 5100~5109
45 R. D. Clark, A. Strizhev, J. M. Leonard, J. F. Blake, and J. B. Matthew. Consensus scoring for ligand/protein interactions. Journal of Molecular Graphics & Modelling. 2002, 20(4): 281~295
46 M. Kontoyianni, L. M. McClellan, and G. S. Sokol. Evaluation of docking performance: Comparative data on docking algorithms. Journal of Medicinal Chemistry. 2004, 47(3): 558~565
47 E. Kellenberger, J. Rodrigo, P. Muller, and D. Rognan. Comparative evaluation of eight docking tools for docking and virtual screening accuracy. Proteins-Structure Function and Bioinformatics. 2004, 57(2): 225~242
48 H. A. Carlson. Protein flexibility and drug design: how to hit a moving target. Current Opinion in Chemical Biology. 2002, 6(4): 447~452
49 H. J. Bohm. Ludi - Rule-Based Automatic Design of New Substituents for Enzyme-Inhibitor Leads. Journal of Computer-Aided Molecular Design. 1992, 6(6): 593~606
50 H. J. Bohm. Prediction of binding constants of protein ligands: A fast method for the prioritization of hits obtained from de novo design or 3D database search programs. Journal of Computer-Aided Molecular Design. 1998, 12(4): 309~323
51 P. J. Goodford. A Computational-Procedure for Determining Energetically Favorable Binding-Sites on Biologically Important Macromolecules. Journal of Medicinal Chemistry. 1985, 28(7): 849~857
52 D. N. A. Boobbyer, P. J. Goodford, P. M. McWhinnie, and R. C. Wade. New Hydrogen-Bond Potentials for Use in Determining Energetically Favorable Binding-Sites on Molecules of Known Structure. Journal of Medicinal Chemistry. 1989, 32(5): 1083~1094
53 R. D. Cramer, D. E. Patterson, and J. D. Bunce. Comparative Molecular-Field Analysis(CoMFA) .1. Effect of Shape on Binding of Steroids to Carrier Proteins. Journal of the American Chemical Society. 1988, 110(18): 5959~5967
54 R. D. Cramer, J. D. Bunce, D. E. Patterson, and I. E. Frank. Cross-Validation, Bootstrapping, and Partial Least-Squares Compared with Multiple-Regression in Conventional Qsar Studies. Quantitative Structure-Activity Relationships. 1988, 7(1): 18~25
55 A. Miranker and M. Karplus. Functionality Maps of Binding-Sites - a Multiple Copy Simultaneous Search Method. Proteins: Structure, Function and Genetics. 1991, 11(1): 29~34
56 R. S. Pearlman and K. M. Smith. EA-Inventor: Using VHTS scoring functions for De novo design. Abstracts of Papers of the American Chemical Society. 2004, 228: U365~U365
57 Y. C. Martin, "Distance comparisons: A new strategy for examining three-dimensional structure-activity relationships," in Classical and Three-Dimensional Qsar in Agrochemistry (Amer Chemical Soc, Washington, 1995), pp. 318~329.
58 G. Jones, P. Willett, and R. C. Glen. A genetic algorithm for flexible molecular overlay and pharmacophore elucidation. Journal of Computer-Aided Molecular Design. 1995, 9(6): 532~549
59 Y. Kurogi and O. F. Guner. Pharmacophore modeling and three-dimensional database searching for drug design using catalyst. Current Medicinal Chemistry. 2001, 8(9): 1035~1055
60 A. Smellie. Poling: Promoting Conformational Variation. Journal of Computational Chemistry. 1995, 16: 171~187
61 Y. Patel, V. J. Gillet, G. Bravi, and A. R. Leach. A comparison of the pharmacophore identification programs: Catalyst, DISCO and GASP. Journal of Computer-Aided Molecular Design. 2002, 16(8-9): 653~681
62 C. Charlier, J. P. Henichart, F. Durant, and J. Wouters. Structural insights into human 5-lipoxygenase inhibition: Combined ligand-based and target-based approach. Journal of Medicinal Chemistry. 2006, 49(1): 186~195
63 C. Hansch, R. M. Muir, T. Fujita, P. P. Maloney, F. Geiger, and M. Streich. The Correlation of Biological Activity of Plant Growth Regulators and Chloromycetin Derivatives with Hammett Constants and Partition Coefficients. Journal of the American Chemical Society. 1963, 85(18): 2817~2824
64 S. M. Free and J. W. Wilson. A Mathematical Contribution to Structure-Activity Studies. Journal of Medicinal Chemistry. 1964, 7(4): 395~399
65 L. B. Kier and L. H. Hall. Molecular Connectivity .7. Specific Treatment of Heteroatoms. Journal of Pharmaceutical Sciences. 1976, 65(12): 1806~1809
66 G. M. Crippen. Distance geometry approach to rationalizing binding data. Journal of Medicinal Chemistry. 1979, 22(8): 988~997
67 A. J. Hopfinger. A QSAR investigation of dihydrofolate reductase inhibition by Baker triazines based upon molecular shape analysis. Journal of the American Chemical Society. 1980, 102(24): 7196~7206
68 A. N. Jain, K. Koile, and D. Chapman. Compass: Predicting Biological Activities from Molecular Surface Properties. Performance Comparisons on a Steroid Benchmark. Journal of Medicinal Chemistry. 1994, 37(15): 2315~2327
69 G. Klebe, U. Abraham, and T. Mietzner. Molecular Similarity Indices in a Comparative Analysis (CoMSIA) of Drug Molecules to Correlate and Predict Their Biological Activity. Journal of Medicinal Chemistry. 1994, 37(24): 4130~4146
70 A. Vedani, K. Briem, M. Dobler, H. Dollinger, and D. R. McMasters. Multiple-conformation andprotonation-state representation in 4D-QSAR: The neurokinin-1 receptor system. Journal of Medicinal Chemistry. 2000, 43(23): 4416~4427
71 A. Vedani and M. Dobler. 5D-QSAR: The key for simulating induced fit? Journal of Medicinal Chemistry. 2002, 45(11): 2139~2149
72 A. Vedani, M. Dobler, and M. A. Lill. Combining protein modeling and 6D-QSAR. Simulating the binding of structurally diverse ligands to the estrogen receptor. Journal of Medicinal Chemistry. 2005, 48(11): 3700~3703
73 W. P. Walters, M. T. Stahl, and M. A. Murcko. Virtual screening - an overview. Drug Discovery Today. 1998, 3(4): 160~178
74 A. C. Good, S. R. Krystek, and J. S. Mason. High-throughput and virtual screening: core lead discovery technologies move towards integration. Drug Discovery Today. 2000, 5(12): S61~S69
75 F. Bajorath. Integration of virtual and high-throughput screening. Nature Reviews Drug Discovery. 2002, 1(11): 882~894
76 H. J. Boehm, M. Boehringer, D. Bur, H. Gmuender, W. Huber, W. Klaus, D. Kostrewa, H. Kuehne, et al. Novel inhibitors of DNA gyrase: 3D structure based biased needle screening, hit validation by biophysical methods, and 3D guided optimization. A promising alternative to random screening. Journal of Medicinal Chemistry. 2000, 43(14): 2664~2674
77 T. N. Doman, S. L. McGovern, B. J. Witherbee, T. P. Kasten, R. Kurumbail, W. C. Stallings, D. T. Connolly, and B. K. Shoichet. Molecular docking and high-throughput screening for novel inhibitors of protein tyrosine phosphatase-1B. Journal of Medicinal Chemistry. 2002, 45(11): 2213~2221
78 A. M. Paiva, D. E. Vanderwall, J. S. Blanchard, J. W. Kozarich, J. M. Williamson, and T. M. Kelly. Inhibitors of dihydrodipicolinate reductase, a key enzyme of the diaminopimelate pathway of Mycobacterium tuberculosis. Biochimica Et Biophysica Acta-Protein Structure and Molecular Enzymology. 2001, 1545(1-2): 67~77
79 李洪林, 沈建华, 罗小民, 沈旭, 朱维良, 王希诚, 陈凯先, and 蒋华良. 虚拟筛选与新药发现. 生命科学. 2000, 17(2): 125~131
80 R. F. Service. Molecules get wired. Science. 2001, 294(5551): 2442~2443
81 M. Melnick, S. H. Reich, K. K. Lewis, L. J. Mitchell, D. Nguyen, A. J. Trippe, H. Dawson, J. F. Davies, et al. Bis tertiary amide inhibitors of the HIV-1 protease generated via protein structure-based iterative design. Journal of Medicinal Chemistry. 1996, 39(14): 2795~2811
82 I. J. Enyedy, Y. Ling, K. Nacro, Y. Tomita, X. H. Wu, Y. Y. Cao, R. B. Guo, B. H. Li, et al. Discovery of small-molecule inhibitors of bcl-2 through structure-based computer screening. Journal of Medicinal Chemistry. 2001, 44(25): 4313~4324
83 I. J. Enyedy, S. L. Lee, A. H. Kuo, R. B. Dickson, C. Y. Lin, and S. M. Wang. Structure-based approach for the discovery of bis-benzamidines as novel inhibitors of matriptase. Journal of Medicinal Chemistry. 2001, 44(9): 1349~1355
84 J. Lalezari, M. Thompson, P. Kumar, P. Piliero, R. Davey, T. Murtaugh, K. Patterson, A. Shachoy-Clark, et al. 873140, a novel CCR5 antagonist: antiviral activity and safety during short-term monotherapy in HIV-infected adults. Presented at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Washington, D.C., October 30 through November 2,Abstract H-1137b. 2004
85 M. D. Barratt and R. A. Rodford. The computational prediction of toxicity. Current Opinion in Chemical Biology. 2001, 5(4): 383~388
86 P. D. Kwong, R. Wyatt, J. Robinson, R. W. Sweet, J. Sodroski, and W. A. Hendrickson. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature. 1998, 393(666): 648~659
87 B. Chen, E. M. Vogan, H. Y. Gong, J. J. Skehel, D. C. Wiley, and S. C. Harrison. Structure of an unliganded simian immunodeficiency virus gp120 core. Nature. 2005, 433(7028): 834~841
88 S. T. D. Hsu and A. M. J. J. Bonvin. Atomic insight into the CD4 binding-induced conformational changes in HIV-1 gp120. Proteins-Structure Function and Bioinformatics. 2004, 55(3): 582~593
89 C. D. Rizzuto, R. Wyatt, N. Hernandez-Ramos, Y. Sun, P. D. Kwong, W. A. Hendrickson, and J. Sodroski. A conserved HIV gp120 glycoprotein structure involved in chemokine receptor binding. Science. 1998, 280(5371): 1949~1953
90 T. Schacker, A. C. Collier, R. Coombs, J. D. Unadkat, I. Fox, J. Alam, J. P. Wang, E. Eggert, et al. Phase-I Study of High-Dose, Intravenous Rscd4 in Subjects with Advanced Hiv-1 Infection. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology. 1995, 9(2): 145~152
91 F. M., O'Neill, M. P., B. D.R., P. P., and O. W., "PRO 542 (CD4-IgG2) has a profound impact on HIV-1 replication in the Hu-PBL-SCID mouse model.," presented at the 9th Conference on Retroviruses and Opportunistic Infections, Seattle, Wash, USA, 2002.
92 K. Ikeda, K. Konishi, M. Sato, H. Hoshino, and K. Tanaka. Inhibition of HIV-1 infection by synthetic peptide analogues derived from the NH2-terminal extracellular region of GPR1. Bioorganic & Medicinal Chemistry Letters. 2001, 11(19): 2607~2609
93 M. Ono, Y. Wada, Y. M. Wu, R. Nemori, Y. Jinbo, H. Wang, K. M. Lo, N. Yamaguchi, et al. FP-21399 blocks HIV envelope protein-mediated membrane fusion and concentrates in lymph nodes. Nature Biotechnology. 1997, 15(4): 343~348
94 T. Wang, Z. X. Zhang, O. B. Wallace, M. Deshpande, H. Q. Fang, Z. Yang, L. M. Zadjura, D. L. Tweedie, et al. Discovery of 4-benzoyl-1-[(4-methoxy-1H-pyrrolo[2,3-b]lpyridin-3-yl)oxoacetyl] -2-(R)- methylpiperazine (BMS-378806): A novel HIV-1 attachment inhibitor that interferes with CD4-gp120 interactions. Journal of Medicinal Chemistry. 2003, 46(20): 4236~4239
95 Q. Guo, H. T. Ho, I. Dicker, L. Fan, N. N. Zhou, J. Friborg, T. Wang, B. V. McAuliffe, et al. Biochemical and genetic characterizations of a novel human immunodeficiency virus type 1 inhibitor that blocks gp120-CD4 interactions. Journal of Virology. 2003, 77(19): 10528~10536
96 P. F. Lin, W. Blair, T. Wang, T. Spicer, Q. Guo, N. N. Zhou, Y. F. Gong, H. G. H. Wang, et al. A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding. Proceedings of the National Academy of Sciences of the United States of America. 2003, 100(19): 11013~11018
97 I. Botos, B. R. O'Keefe, S. R. Shenoy, L. K. Cartner, D. M. Ratner, P. H. Seeberger, M. R. Boyd, and A. Wlodawer. Structures of the complexes of a potent anti-HIV protein cyanovirin-N and high mannose oligosaccharides. Journal of Biological Chemistry. 2002, 277(37): 34336~34342
98 J. O. Ojwang, R. W. Buckheit, Y. Pommier, A. Mazumder, K. Devreese, J. A. Este, D. Reymen, L. A. Pallansch, et al. T30177, an Oligonucleotide Stabilized by an Intramolecular Guanosine Octet, Is a Potent Inhibitor of Laboratory Strains and Clinical Isolates of Human- Immunodeficiency -Virus Type-1. Antimicrobial Agents and Chemotherapy. 1995, 39(11): 2426~2435
99 J. A. Este, C. Cabrera, D. Schols, P. Cherepanov, A. Gutierrez, M. Witvrouw, C. Pannecouque, Z. Debyser, et al. Human immunodeficiency virus glycoprotein gp120 as the primary target for the antiviral action of AR177 (Zintevir). Molecular Pharmacology. 1998, 53(2): 340~345
100 E. Lindahl, B. Hess, and D. van der Spoel. GROMACS 3.0: a package for molecular simulation and trajectory analysis. Journal of Molecular Modeling. 2001, 7(8): 306~317
101 X. Daura, A. E. Mark, and W. F. van Gunsteren. Parametrization of aliphatic CHn united atoms of GROMOS96 force field. Journal of Computational Chemistry. 1998, 19(5): 535~547
102 H. J. C. Berendsen, J. P. M. Postma, W. F. van Gunsteren, and J. Hermans, Interaction models for water in relation to protein hydration, Intermolecular Forces (Reidel Publishing Company, 1981), pp. 331~342.
103 H. J. C. Berendsen, J. P. M. Postma, W. F. Vangunsteren, A. Dinola, and J. R. Haak. Molecular-Dynamics with Coupling to an External Bath. Journal of Chemical Physics. 1984, 81(8): 3684~3690
104 B. Hess, H. Bekker, H. J. C. Berendsen, and J. Fraaije. LINCS: A linear constraint solver for molecular simulations. Journal of Computational Chemistry. 1997, 18(12): 1463~1472
105 S. J. Weiner, P. A. Kollman, D. A. Case, U. C. Singh, C. Ghio, G. Alagona, S. Profeta, and P. Weiner. A New Force-Field for Molecular Mechanical Simulation of Nucleic-Acids and Proteins. Journal of the American Chemical Society. 1984, 106(3): 765~784
106 M. Clark, R. D. Cramer, and N. Vanopdenbosch. Validation of the General-Purpose Tripos 5.2 Force-Field. Journal of Computational Chemistry. 1989, 10(8): 982~1012
107 A. W. Schuttelkopf and D. M. F. van Aalten. PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallographica Section D-Biological Crystallography. 2004, 60: 1355~1363
108 N. Madani, A. L. Perdigoto, K. Srinivasan, J. M. Cox, J. J. Chruma, J. LaLonde, M. Head, A. B. Smith, et al. Localized changes in the gp120 envelope glycoprotein confer resistance to human immunodeficiency virus entry inhibitors BMS-806 and #155. Journal of Virology. 2004, 78(7): 3742~3752
109 U. Moebius, L. K. Clayton, S. Abraham, S. C. Harrison, and E. L. Reinherz. The Human Immunodeficiency Virus-Gp120 Binding-Site on Cd4 - Delineation by Quantitative Equilibrium and Kinetic Binding-Studies of Mutants in Conjunction with a High-Resolution Cd4 Atomic-Structure. Journal of Experimental Medicine. 1992, 176(2): 507~517
110 R. W. Sweet, A. Truneh, and W. A. Hendrickson. CD4 - Its Structure, Role in Immune Function and Aids Pathogenesis, and Potential as a Pharmacological Target. Current Opinion in Biotechnology. 1991, 2(4): 622~633
111 J. S. Wang, N. Le, A. Heredia, H. J. Song, R. Redfield, and L. X. Wang. Modification and structure-activity relationship of a small molecule HIV-1 inhibitor targeting the viral envelope glycoprotein gp120. Organic & Biomolecular Chemistry. 2005, 3(9): 1781~1786
112 S. H. Xiang, P. D. Kwong, R. Gupta, C. D. Rizzuto, D. J. Casper, R. Wyatt, L. P. Wang, W. A. Hendrickson, et al. Mutagenic stabilization and/or disruption of a CD4-bound state reveals distinct conformations of the human immunodeficiency virus type 1 gp120 envelope glycoprotein. Journal of Virology. 2002, 76(19): 9888~9899
113 Z. H. Si, N. Madani, J. M. Cox, J. J. Chruma, J. C. Klein, A. Schon, N. Phan, L. Wang, et al. Small-molecule inhibitors of HIV-1 entry block receptor-induced conformational changes in the viral envelope glycoproteins. Proceedings of the National Academy of Sciences of the United States of America. 2004, 101(14): 5036~5041
114 H. J. P. Ryser and R. Fluckiger. Keynote review: Progress in targeting HIV-1 entry. Drug Discovery Today. 2005, 10(16): 1085~1094
115 C. M. Carr and P. S. Kim. A Spring-Loaded Mechanism for the Conformational Change of Influenza Hemagglutinin. Cell. 1993, 73(4): 823~832
116 D. C. Chan and P. S. Kim. HIV Entry and Its Inhibition. Cell. 1998, 93(5): 681~684
117 D. C. Chan, C. T. Chutkowski, and P. S. Kim. Evidence that a prominent cavity in the coiled coil of HIV type 1 gp41 is an attractive drug target. Proceedings of the National Academy of Sciences of the United States of America. 1998, 95(26): 15613~15617
118 L. T. Rimsky, D. C. Shugars, and T. J. Matthews. Determinants of human immunodeficiency virus type 1 resistance to gp41-derived inhibitory peptide. Journal of Virology. 1998, 72(2): 986~993
119 J. Cao, L. Bergeron, E. Helseth, M. Thali, H. Repke, and J. Sodroski. Effects of Amino-Acid Changes in the Extracellular Domain of the Human-Immunodeficiency-Virus Type-1 Gp41 Envelope Glycoprotein. Journal of Virology. 1993, 67(5): 2747~2755
120 H. M. Mo, A. K. Konstantinidis, K. D. Stewart, T. Dekhtyar, T. Ng, K. Swift, E. D. Matayoshi, W. Kati, et al. Conserved residues in the coiled-coil pocket of human immunodeficiency virus type 1 gp41 are essential for viral replication and interhelical interaction. Virology. 2004, 329(2): 319~327
121 M. Lu, M. O. Stoller, S. Wang, J. Liu, M. B. Fagan, and J. H. Nunberg. Structural and Functional Analysis of Interhelical Interactions in the Human Immunodeficiency Virus Type 1 gp41 Envelope Glycoprotein by Alanine-Scanning Mutagenesis. Journal of Virology. 2001, 75(22): 11146~11156
122 H. B. Bernstein, S. P. Tucker, S. R. Kar, S. A. McPherson, D. T. McPherson, J. W. Dubay, J. Lebowitz, R. W. Compans, et al. Oligomerization of the Hydrophobic Heptad Repeat of Gp41. Journal of Virology. 1995, 69(5): 2745~2750
123 P. Poumbourios, K. A. Wilson, R. J. Center, W. ElAhmar, and B. E. Kemp. Human immunodeficiency virus type 1 envelope glycoprotein oligomerization requires the gp41 amphipathic alpha-helical/leucine zipper-like sequence. Journal of Virology. 1997, 71(3): 2041~2049
124 J. M. Kilby, S. Hopkins, T. M. Venetta, B. DiMassimo, G. A. Cloud, J. Y. Lee, L. Alldredge, E. Hunter, et al. Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nature Medicine. 1998, 4(11): 1302~1307
125 V. Oldfield, G. M. Keating, and G. Plosker. Enfuvirtide - A review of its use in the management of HIV infection. Drugs. 2005, 65(8): 1139~1160
126 J. M. Kilby, J. P. Lalezari, J. J. Eron, M. Carlson, C. Cohen, R. C. Arduino, J. C. Goodgame, J. E. Gallant, et al. The safety, plasma pharmacokinetics, and antiviral activity of subcutaneous enfuvirtide (T-20), a peptide inhibitor of gp41-mediated virus fusion, in HIV-infected adults. Aids Research and Human Retroviruses. 2002, 18(10): 685~693
127 C. Wild, T. Oas, C. McDanal, D. Bolognesi, and T. Matthews. A Synthetic Peptide Inhibitor of Human-Immunodeficiency-Virus Replication - Correlation between Solution Structure and Viral Inhibition. Proceedings of the National Academy of Sciences of the United States of America. 1992, 89(21): 10537~10541
128 S. B. Jiang, K. Lin, N. Strick, and A. R. Neurath. HIV-1 Inhibition by a Peptide. Nature. 1993, 365(6442): 113
129 C. T. Wild, D. C. Shugars, T. K. Greenwell, C. B. McDanal, and T. J. Matthews. Peptides Corresponding to a Predictive Alpha-Helical Domain of Human-Immunodeficiency-Virus Type-1Gp41 Are Potent Inhibitors of Virus-Infection. Proceedings of the National Academy of Sciences of the United States of America. 1994, 91(21): 9770~9774
130 M. Lu, S. C. Blacklow, and P. S. Kim. A Trimeric Structural Domain of the HIV-1 Transmembrane Glycoprotein. Nature Structural Biology. 1995, 2(12): 1075~1082
131 M. Lu and P. S. Kim. A trimeric structural subdomain of the HIV-1 transmembrane glycoprotein. Journal of Biomolecular Structure & Dynamics. 1997, 15(3): 465~471
132 X. P. Zhang, K. Nieforth, J. M. Lang, R. Rouzier-Panis, J. Reynes, A. Dorr, S. Kolis, M. R. Stiles, et al. Pharmacokinetics of plasma enfuvirtide after subcutaneous administration to patients with human immunodeficiency virus: Inverse Gaussian density absorption and 2-compartment disposition. Clinical Pharmacology & Therapeutics. 2002, 72(1): 10~19
133 J. J. Eron, R. M. Gulick, J. A. Bartlett, T. Merigan, R. Arduino, J. M. Kilby, B. Yangco, A. Diers, et al. Short-term safety and antiretroviral activity of T-1249, a second-generation fusion inhibitor of HIV. Journal of Infectious Diseases. 2004, 189(6): 1075~1083
134 L. Martin-Carbonero. Discontinuation of the clinical development of fusion inhibitor T-1249. Aids Reviews. 2004, 6(1): 61
135 D. M. Eckert, V. N. Malashkevich, L. H. Hong, P. A. Carr, and P. S. Kim. Inhibiting HIV-1 Entry: Discovery of D-Peptide Inhibitors that Target the gp41 Coiled-Coil Pocket. Cell. 1999, 99(1): 103~115
136 A. Otaka, M. Nakamura, D. Nameki, E. Kodama, S. Uchiyama, S. Nakamura, H. Nakano, H. Tamamura, et al. Remodeling of gp41-C34 peptide leads to highly effective inhibitors of the fusion of HIV-1 with target cells. Angewandte Chemie-International Edition. 2002, 41(16): 2938~2940
137 J. K. Judice, J. Y. K. Tom, W. Huang, T. Wrin, J. Vennari, C. J. Petropoulos, and R. S. McDowell. Inhibition of HIV type 1 infectivity by constrained alpha-helical peptides: Implications for the viral fusion mechanism. Proceedings of the National Academy of Sciences of the United States of America. 1997, 94(25): 13426~13430
138 S. K. Sia, P. A. Carr, A. G. Cochran, V. N. Malashkevich, and P. S. Kim. Short constrained peptides that inhibit HIV-1 entry. Proceedings of the National Academy of Sciences of the United States of America. 2002, 99(23): 14664~14669
139 D. M. Eckert and P. S. Kim. Design of potent inhibitors of HIV-1 entry from the gp41 N-peptide region. Proceedings of the National Academy of Sciences of the United States of America. 2001, 98(20): 11187~11192
140 C. A. Bewley, J. M. Louis, R. Ghirlando, and G. M. Clore. Design of a novel peptide inhibitor of HIV fusion that disrupts the internal trimeric coiled-coil of gp41. Journal of Biological Chemistry. 2002, 277(16): 14238~14245
141 M. J. Root, M. S. Kay, and P. S. Kim. Protein design of an HIV-1 entry inhibitor. Science. 2001, 291(5505): 884~888
142 M. J. Root and H. K. Steger. HIV-1 gp41 as a target for viral entry inhibition. Current Pharmaceutical Design. 2004, 10(15): 1805~1825
143 M. J. Root and D. H. Hamer. Targeting therapeutics to an exposed and conserved binding element of the HIV-1 fusion protein. Proceedings of the National Academy of Sciences of the United States of America. 2003, 100(9): 5016~5021
144 L. Ni, G. F. Gao, and P. Tien. Rational design of highly potent HIV-1 fusion inhibitory proteins: Implication for developing antiviral therapeutics. Biochemical and Biophysical ResearchCommunications. 2005, 332(3): 831~836
145 R. M. Markosyan, X. W. Maj, F. S. Cohen, and G. B. Melikyan. The mechanism of inhibition of HIV-1 env-mediated cell-cell fusion by recombinant cores of gp41 ectodomain. Virology. 2002, 302(1): 174~184
146 J. M. Louis, C. A. Bewley, and G. M. Clore. Design and properties of N-CCG-gp41, a chimeric gp41 molecule with nanomolar HIV fusion inhibitory activity. Journal of Biological Chemistry. 2001, 276(31): 29485~29489
147 H. Ji, W. Shu, F. T. Burling, S. B. Jiang, and M. Lu. Inhibition of human immunodeficiency virus type 1 infectivity by the gp41 core: Role of a conserved hydrophobic cavity in membrane fusion. Journal of Virology. 1999, 73(10): 8578~8586
148 S. B. Jiang, K. Lin, L. Zhang, and A. K. Debnath. A screening assay for antiviral compounds targeted to the HIV-1 gp41 core structure using a conformation-specific monoclonal antibody. Journal of Virological Methods. 1999, 80(1): 85~96
149 S. Jiang, K. Lin, and M. Lu. A conformation-specific monoclonal antibody reacting with fusion-active gp41 from the human immunodeficiency virus type 1 envelope glycoprotein. Journal of Virology. 1998, 72(12): 10213~10217
150 S. W. Liu, L. Boyer-Chatenet, H. Lu, and S. B. Jiang. Rapid and automated fluorescence-linked immunosorbent assay for high-throughput screening of HIV-1 fusion inhibitors targeting gp41. Journal of Biomolecular Screening. 2003, 8(6): 685~693
151 L. A. Hong, Q. Zhao, Z. K. Xu, and S. B. Jiang. Automatic quantitation of HIV-1 mediated cell-to-cell fusion with a digital image analysis system (DIAS): application for rapid screening of HIV-1 fusion inhibitors. Journal of Virological Methods. 2003, 107(2): 155~161
152 A. K. Debnath, L. Radigan, and S. Jiang. Structure-Based Identification of Small Molecule Antiviral Compounds Targeted to the gp41 Core Structure of the Human Immunodeficiency Virus Type 1. Journal of Medicinal Chemistry 1999, 42(17): 3203~3209
153 K. P. Naicker, S. B. Jiang, H. Lu, J. H. Ni, L. Boyer-Chatenet, L. X. Wang, and A. K. Debnath. Synthesis and anti-HIV-1 activity of 4-[4-(4,6-bisphenylamino-[1,3,5]triazin-2-ylamino)-5- methoxy-2-methylphe nylazo]-5-hydroxynaphthalene-2,7-disulfonic acid and its derivatives. Bioorganic and Medicinal Chemistry. 2004, 12(5): 1215~1220
154 Q. Zhao, J. T. Ernst, A. D. Hamilton, A. K. Debnath, and S. B. Jiang. XTT formazan widely used to detect cell viability inhibits HIV type 1 infection in vitro by targeting gp41. Aids Research and Human Retroviruses. 2002, 18(14): 989~997
155 S. B. Jiang, H. Lu, S. W. Liu, Q. Zhao, Y. X. He, and A. K. Debnath. N-substituted pyrrole derivatives as novel human immunodeficiency virus type 1 entry inhibitors that interfere with the gp41 six-helix bundle formation and block virus fusion. Antimicrobial Agents and Chemotherapy. 2004, 48(11): 4349~4359
156 J. T. Ernst, O. Kutzki, A. K. Debnath, S. Jiang, H. Lu, and A. D. Hamilton. Design of a protein surface antagonist based on alpha-helix mimicry: Inhibition of gp41 assembly and viral fusion. Angewandte Chemie-International Edition. 2002, 41(2): 278~281
157 Y. Xu, H. Lu, J. P. Kennedy, X. X. Yan, L. A. McAllister, N. Yamamoto, J. A. Moss, G. E. Boldt, et al. Evaluation of "credit card" libraries for inhibition of HIV-1 gp41 fusogenic core formation. Journal of Combinatorial Chemistry. 2006, 8(4): 531~539
158 S. W. Liu, H. Lu, Q. Zhao, Y. X. He, J. K. Niu, A. K. Debnath, S. G. Wu, and S. B. Jiang. Theaflavin derivatives in black tea and catechin derivatives in green tea inhibit HIV-1 entry bytargeting gp41. Biochimica Et Biophysica Acta-General Subjects. 2005, 1723(1-3): 270~281
159 S. Lee-Huang, P. L. Huang, D. Zhang, J. W. Lee, J. Bao, Y. Sun, Y.-T. Chang, J. Zhang, et al. Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol: Part I. Integrase inhibition. Biochemical and Biophysical Research Communications. 2007, 354(4): 872~878
160 J. Bao, D. W. Zhang, J. Z. H. Zhang, P. L. Huang, P. L. Huang, and S. Lee-Huang. Computational study of bindings of olive leaf extract (OLE) to HIV-1 fusion protein gp41. FEBS Letters. 2007, 581(14): 2737~2742
161 R. X. Wang, Y. Gao, and L. H. Lai. LigBuilder: A multi-purpose program for structure-based drug design. Journal of Molecular Modeling. 2000, 6(7-8): 498~516
162 A. C. Wallace, R. A. Laskowski, and J. M. Thornton. Ligplot - a Program to Generate Schematic Diagrams of Protein Ligand Interactions. Protein Engineering. 1995, 8(2): 127~134
163 C. Bissantz, G. Folkers, and D. Rognan. Protein-based virtual screening of chemical databases. 1. Evaluation of different docking/scoring combinations. Journal of Medicinal Chemistry. 2000, 43(25): 4759~4767
164 M. A. Miteva, W. H. Lee, M. O. Montes, and B. O. Villoutreix. Fast Structure-Based Virtual Ligand Screening Combining FRED, DOCK, and Surflex. Journal of Medicinal Chemistry. 2005, 48(19): 6012~6022
165 R. G. Gould and W. A. Jacobs. The Synthesis of Certain Substituted Quinolines and
5,6-Benzoquinolines. Journal of the American Chemical Society. 1939, 61(10): 2890~2895
166 Y. F. Suen, L. Robins, B. X. Yang, A. S. Verkman, M. H. Nantz, and M. J. Kurth. Sulfamoyl-4-oxoquinoline-3-carboxamides: Novel potentiators of defective Delta F508-cystic fibrosis transmembrane conductance regulator chloride channel gating. Bioorganic & Medicinal Chemistry Letters. 2006, 16(3): 537~540
167 D. Farcasiu, J. Jahme, and C. Ruchardt. Relative Reactivity of Bridgehead Adamantyl and Homoadamantyl Substrates from Solvolyses with Heptafluorobutyrate as a Highly Reactive Carboxylate Leaving Group - Absence of Sn2 Character of Solvolysis of Tert-Butyl Derivatives. Journal of the American Chemical Society. 1985, 107(20): 5717~5722
168 K. Kettler, J. Sakowski, J. Wiesner, R. Ortmann, H. Jomaa, and M. Schlitzer. Novel lead structures for antimalarial farnesyltransferase inhibitors. Pharmazie. 2005, 60(5): 323~327
169 C. G. Dave and H. A. Joshipura. Microwave assisted Gould-Jacob reaction: Synthesis of 4-quinolones under solvent free conditions. Indian Journal of Chemistry Section B-Organic Chemistry Including Medicinal Chemistry. 2002, 41(3): 650~652
170 H. K. Deng, R. Liu, W. Ellmeier, S. Choe, D. Unutmaz, M. Burkhart, P. DiMarzio, S. Marmon, et al. Identification of a major co-receptor for primary isolates of HIV-1. Nature. 1996, 381(6584): 661~666
171 L. J. Wu, N. P. Gerard, R. Wyatt, H. Choe, C. Parolin, N. Ruffing, A. Borsetti, A. A. Cardoso, et al. CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5. Nature. 1996, 384(6605): 179~183
172 R. Jahn, T. Lang, and T. C. Sudhof. Membrane fusion. Cell. 2003, 112(4): 519~533
173 M. Samson, F. Libert, B. J. Doranz, J. Rucker, C. Liesnard, C. M. Farber, S. Saragosti, C. Lapoumeroulie, et al. Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature. 1996, 382(6593): 722~725
174 S. G. Mills and J. A. DeMartino. Chemokine receptor-directed agents as novel anti-HIV-1therapies. Current topics in Medicinal Chemistry. 2004, 4: 1017~1034
175 K. Maeda, H. Nakata, H. Ogata, Y. Koh, T. Miyakawa, and H. Mitsuya. The current status of, and challenges in, the development of CCR5 inhibitors as therapeutics for HIV-1 infection. Current Opinion in Pharmacology. 2004, 4(5): 447~452
176 M. Baba, O. Nishimura, N. Kanzaki, M. Okamoto, H. Sawada, Y. Iizawa, M. Shiraishi, Y. Aramaki, et al. A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proceedings of the National Academy of Sciences of the United States of America. 1999, 96(10): 5698~5703
177 M. Shiraishi, Y. Aramaki, M. Seto, H. Imoto, Y. Nishikawa, N. Kanzaki, M. Okamoto, H. Sawada, et al. Discovery of novel, potent, and selective small-molecule CCR5 antagonists as anti-HIV-1 agents: Synthesis and biological evaluation of anilide derivatives with a quaternary ammonium moiety. Journal of Medicinal Chemistry. 2000, 43(10): 2049~2063
178 J. M. Strizki, S. Xu, N. E. Wagner, L. Wojcik, J. Liu, Y. Hou, M. Endres, A. Palani, et al. SCH-C (SCH 351125), an orally bioavailable, small molecule antagonist of the chemokine receptor CCR5, is a potent inhibitor of HIV-1 infection in vitro and in vivo. Proceedings of the National Academy of Sciences of the United States of America. 2001, 98(22): 12718~12723
179 J. R. Tagat, S. W. McCombie, D. Nazareno, M. A. Labroli, Y. S. Xiao, R. W. Steensma, J. M. Strizki, B. M. Baroudy, et al. Piperazine-based CCR5 antagonists as HIV-1 inhibitors. IV. Discovery of 1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]-4-[4-{2-methoxy-1(R)-4-(trifluoromethyl) -phenyl}ethyl-3(S)-methyl-1-piperazinyl]-4-methylpiperidine (Sch-417690/Sch-D), a potent, highly selective, and orally bioavailable CCR5 antagonist. Journal of Medicinal Chemistry. 2004, 47(10): 2405~2408
180 A. L. Pozniak, G. Fatkenheuer, M. Johnson, I. M. Hoepelman, J. Rockstroh, F. Goebel, S. Abel, I. James, et al., "Effect of short-term monotherapy with UK-427,857 on viral load in HIV-infected patients," (Chicago, 2003).
181 W. Kazmierski, N. Bifulco, H. B. Yang, L. Boone, F. DeAnda, C. Watson, and T. Kenakin. Recent progress in discovery of small-molecule CCR5 chemokine receptor ligands as HIV-1 inhibitors. Bioorganic and Medicinal Chemistry. 2003, 11(13): 2663~2676
182 K. Maeda, K. Yoshimura, S. Shibayama, H. Habashita, H. Tada, K. Sagwa, T. Miyakawa, M. Aoki, et al. Novel low molecular weight spirodiketopiperazine derivatives potently inhibit R5 HIV-1 infection through their antagonistic effects on CCR5. Journal of Biological Chemistry. 2001, 276: 35194~35200
183 K. Maeda, H. Nakata, Y. Koh, T. Miyakawa, H. Ogata, Y. Takaoka, S. Shibayama, K. Sagawa, et al. Spirodiketopiperazine-based CCR5 inhibitor which preserves CC-Chemokine/CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus type 1 in vitro. Journal of Virology. 2004, 78(16): 8654~8662
184 K. Shankaran, K. L. Donnelly, S. K. Shah, C. G. Caldwell, P. Chen, P. E. Finke, B. Oates, M. MacCoss, et al. Syntheses and biological evaluation of 5-(piperidin-1-yl)-3-phenyl-pentylsulfones as CCR5 antagonists. Bioorganic and Medicinal Chemistry Letters. 2004, 14(13): 3589~3593
185 M. Shu, J. L. Loebach, K. A. Parker, S. G. Mills, K. T. Chapman, D.-M. Shen, L. Malkowitz, M. S. Springer, et al. Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 3: SAR studies on the benzylpyrazole segment. Bioorganic and Medicinal Chemistry Letters. 2004, 14(4): 947~952
186 C. P. Dorn, P. E. Finke, B. Oates, R. J. Budhu, S. G. Mills, M. MacCoss, L. Malkowitz, M. S.Springer, et al. Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 1: Discovery and initial structure–activity relationships for 1-amino-2-phenyl-4-(piperidin-1-yl)butanes. Bioorganic and Medicinal Chemistry Letters. 2001, 11(2): 259~264
187 P. E. Finke, L. C. Meurer, B. Oates, S. G. Mills, M. MacCoss, L. Malkowitz, M. S. Springer, B. L. Daugherty, et al. Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 2: structure–activity relationships for substituted 2-aryl-1-[N-(methyl)-N-(phenylsulfonyl)amino] -4-(piperidin-1-yl)butanes. Bioorganic and Medicinal Chemistry Letters. 2001, 11(2): 265~270
188 P. E. Finke, L. C. Meurer, B. Oates, S. K. Shah, J. L. Loebach, S. G. Mills, M. MacCoss, L. Castonguay, et al. Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 3: A proposed pharmacophore model for 1-[N-(methyl)-N-(phenylsulfonyl)amino]-2-(phenyl)-4-[4- (substituted)piperidin-1-yl]butanes. Bioorganic and Medicinal Chemistry Letters. 2001, 11(18): 2469~2473
189 P. E. Finke, B. Oates, S. G. Mills, M. MacCoss, L. Malkowitz, M. S. Springer, S. L. Gould, J. A. DeMartino, et al. Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 4: synthesis and structure–Activity relationships for 1-[N-(Methyl)-N-(phenylsulfonyl)amino]-2-(phenyl)-4- (4-(N-(alkyl)-N-(benzyloxycarbonyl)amino)piperidin-1-yl)butanes. Bioorganic and Medicinal Chemistry Letters. 2001, 11(18): 2475~2479
190 C. L. Lynch, A. L. Gentry, J. J. Hale, S. G. Mills, M. MacCoss, L. Malkowitz, M. S. Springer, S. L. Gould, et al. CCR5 antagonists: bicyclic isoxazolidines as conformationally constrained N-1-substituted pyrrolidines. Bioorganic and Medicinal Chemistry Letters. 2002, 12(4): 677~679
191 C. A. Willoughby, S. C. Berk, K. G. Rosauer, S. Degrado, K. T. Chapman, S. L. Gould, M. S. Springer, L. Malkowitz, et al. Combinatorial synthesis of CCR5 antagonists. Bioorganic and Medicinal Chemistry Letters. 2001, 11(24): 3137~3141
192 D. Kim, L. Wang, C. G. Caldwell, P. Chen, P. E. Finke, B. Oates, M. MacCoss, S. G. Mills, et al. Design, synthesis, and SAR of heterocycle-containing antagonists of the human CCR5 receptor for the treatment of HIV-1 infection. Bioorganic and Medicinal Chemistry Letters. 2001, 11(24): 3103~3106
193 D. Kim, L. Wang, C. G. Caldwell, P. Chen, P. E. Finke, B. Oates, M. MacCoss, S. G. Mills, et al. Discovery of human CCR5 antagonists containing hydantoins for the treatment of HIV-1 infection. Bioorganic and Medicinal Chemistry Letters. 2001, 11(24): 3099~3102
194 J. N. Burrows, J. G. Cumming, S. M. Fillery, G. A. Hamlin, J. A. Hudson, R. J. Jackson, S. McLaughlin, and J. S. Shaw. Modulators of the human CCR5 receptor. Part 1: Discovery and initial SAR of 1-(3,3-diphenylpropyl)-piperidinyl amides and ureas. Bioorganic and Medicinal Chemistry Letters. 2005, 15(1): 25~28
195 J. G. Cumming, S. J. Brown, A. E. Cooper, A. W. Faull, A. P. Flynn, K. Grime, J. Oldfield, J. S. Shaw, et al. Modulators of the human CCR5 receptor. Part 3: SAR of substituted 1-[3-(4- methanesulfonylphenyl)-3-phenylpropyl]-piperidinyl phenylacetamides. Bioorganic & Medicinal Chemistry Letters. 2006, 16(13): 3533~3536
196 D. A Kim, L. Wang, J. J. Hale, C. L. Lynch, R. J. Budhu, M. MacCoss, S. G. Mills, L. Malkowitz, et al. Potent 1,3,4-trisubstituted pyrrolidine CCR5 receptor antagonists: effects of fused heterocycles on antiviral activity and pharmacokinetic properties. Bioorganic and Medicinal Chemistry Letters. 2005, 15(8): 2129~2134
197 C. A. Willoughby, K. G. Rosauer, J. J. Hale, R. J. Budhu, S. G. Mills, K. T. Chapman, M. MacCoss, L. Malkowitz, et al. 1,3,4 trisubstituted pyrrolidine CCR5 receptor antagonists bearing 4-aminoheterocycle substituted piperidine side chains. Bioorganic and Medicinal Chemistry Letters. 2003, 13(3): 427~431
198 J. J. Hale, R. J. Budhu, S. G. Mills, M. MacCoss, L. Malkowitz, S. Siciliano, S. L. Gould, J. A. DeMartino, et al. 1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 1: discovery of the pyrrolidine scaffold and determination of its stereochemical requirements. Bioorganic and Medicinal Chemistry Letters. 2001, 11(11): 1437~1440
199 J. J. Hale, R. J. Budhu, E. B. Holson, P. E. Finke, B. Oates, S. G. Mills, M. MacCoss, S. L. Gould, et al. 1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 2: lead optimization affording selective, orally bioavailable compounds with potent Anti-HIV activity. Bioorganic and Medicinal Chemistry Letters. 2001, 11(20): 2741~2745
200 J. J. Hale, R. J. Budhu, S. G. Mills, M. MacCoss, S. L. Gould, J. A. DeMartino, M. S. Springer, S. J. Siciliano, et al. 1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 3: polar functionality and its effect on anti-HIV-1 activity. Bioorganic and Medicinal Chemistry Letters. 2002, 12(20): 2997~3000
201 C. L. Lynch, J. J. Hale, R. J. Budhu, A. L. Gentry, S. G. Mills, K. T. Chapman, M. MacCoss, L. Malkowitz, et al. 1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 4: Synthesis of N-1 acidic functionality affording analogues with enhanced antiviral activity against HIV. Bioorganic and Medicinal Chemistry Letters. 2002, 12(20): 3001~3004
202 S. J. Siciliano, S. E. Kuhmann, Y. Weng, N. Madani, M. S. Springer, J. E. Lineberger, R. Danzeisen, M. D. Miller, et al. A critical site in the core of the CCR5 chemokine receptor required for binding and infectivity of human immunodeficiency virus type 1. Journal of Biological Chemistry. 1999, 274: 1905~1913
203 O. F. Güner, Pharmacophore Perception, Development and Use in Drug Design (International University Line:La Jolla, CA, 1999).
204 Y. Xu, H. Liu, C. Y. Niu, C. Luo, X. M. Luo, J. H. Shen, K. X. Chen, and H. L. Jiang. Molecular docking and 3D QSAR studies on 1-amino-2-phenyl-4-(piperidin-1-yl)-butanes based on the structural modeling of human CCR5 receptor. Bioorganic and Medicinal Chemistry. 2004, 12(23): 6193~6208
205 M. S. Song, C. M. Breneman, and N. Sukumar. Three-dimensional quantitative structure-activity relationship analyses of piperidine-based CCR5 receptor antagonists. Bioorganic and Medicinal Chemistry. 2004, 12(2): 489~499