基于受体或配体结构的分子设计与研究
摘要
合理的药物分子设计是新药研究和开发过程中的重要的环节，它对于缩短成药周期，降低药物成本具有重要的现实意义。随着计算机硬件及软件的发展，计算机辅助药物分子设计(Computer Aided Drug Design，CADD)手段己广泛地应用到药物创制过程中，且发挥着越来越重要的作用。基于这一认识，本文开展了如下几个方面的工作。
1．基于结构的环氧合酶-2选择性抑制剂的设计和研究
环氧合酶-2的发现为研究毒副作用小的非甾体抗炎药提供了新的分子靶标，为了设计环氧合酶-2的新型抑制剂，本文进行了以下四方面的工作：
(1)利用比较分子力场分析方法建立了44个选择性环氧合酶-2抑制剂的三维定量构效模型。为进行比较分子力场分析研究，本工作首次通过抑制剂与环氧合酶-2对接(DOCK)，以此确定分子叠合模式，根据这一方法建立的三维定量构效模型不仅比常规比较分子力场建立的模型具有更高的预测能力，而且全面地解释了已有的构效关系，模型映射的受体性质与晶体结构提示的信息是一致的。以此模型提示的三维信息，本文共设计了六类选择性环氧合酶-2抑制剂，活性预测表明它们具有合成价值。目前，已合成了部分化合物，药理活性筛选正在进行之中。
(2)利用对接程序建立了结构差别较大的三环类，NS-398类抑制剂，及吲哚美辛同环氧合酶-2的结合能与抑制活性的相关方程。在建立该模型的同时，解释了NS-398类抑制剂虽然没有三环系化合物的中间桥连环，但是由于这类化合物的硝基与酶形成了氢键作用使得它们仍然具有较高的抑制活性。
(3)利用分子图形学用定量和定性的方法，阐明了环氧合酶-2和环氧合酶-1同相应的抑制剂选择性结合的原因。
(4)根据构象分析以及配体／受体复合物的三维结构，定义了药效团模型，对NCI-3D(National Cancer Institute，美国国家癌症研究所)和Maybridge-3D数据库进行三维结构搜索，共发现15个有可能具有COX-2选择性抑制活性的化合物，这些化合物结构信息的获得，为下一步的合成提供了新的结构骨架。
2．抗肿瘤药紫杉醇的三维定量构效关系研究
紫杉醇具有明显的抗肿瘤活性，目前己用于临床治疗乳腺癌和子宫癌。由于它的水溶性低且具有一些副作用等缺点，有关的紫杉醇的结构修饰仍在继续中。本文选择
Rational drug design is a critical step in pharmaceutical industry. The development of computer hardware and software make it possible to rationally design new drug with computer-aided drug design (CADD), CADD contribute not only to the design of potent compounds, but to many of the steps of going "from concept to clinic". In this thesis, we studied several projects by CADD as follows.
1. Structure-Based Design of Selective Cyclooxygenase-2 (COX-2) Inhibitors
The discovery of COX-2 provided a new target for the design of nonsteroidal anti-inflammatory Drugs (NSAIDs) with less side effects. In order to disclose the relationship between the activity and structure, the studies contained four aspects:
(1)A series of 44 selective COX-2 inhibitors were investigated with the aim of developing a 3D-QSAR model using the comparative molecular field analysis (CoMFA). The active conformation was extracted from the SC-558/COX-2 complex but the alignment of the molecule was performed through two approaches, one is atom to atom operation, the other is determined by DOCK. The model from DOCK alignment shows higher ability to explain and predict the activity of selective COX-2 inhibitor than the model from the classical atom to atom alignment. The feature of this 3D-model are consistent with the binding pocket. According to the model derived from DOCK-based CoMFA, six classes of inhibitors of COX-2 were designed, five of which have been synthesized and their activities assay are being tested.
(2)By using DOCK program, the relationship between activity and binding energy for tricycle inhibitors, NS-398 analogues and Indomethacin was constructed. In addition, DOCK mimics the binding of NS-398 analogues to COX-2, and the results indicated that NS-398 analogues possess higher activity because of the presence of additional hydrogen-bondings.
(3) In order to understand the specificity of COX-2 and COX-1, selective COX-2 and non-selective inhibitors were docked into COX-1 and COX-
1．基于结构的环氧合酶-2选择性抑制剂的设计和研究
环氧合酶-2的发现为研究毒副作用小的非甾体抗炎药提供了新的分子靶标，为了设计环氧合酶-2的新型抑制剂，本文进行了以下四方面的工作：
(1)利用比较分子力场分析方法建立了44个选择性环氧合酶-2抑制剂的三维定量构效模型。为进行比较分子力场分析研究，本工作首次通过抑制剂与环氧合酶-2对接(DOCK)，以此确定分子叠合模式，根据这一方法建立的三维定量构效模型不仅比常规比较分子力场建立的模型具有更高的预测能力，而且全面地解释了已有的构效关系，模型映射的受体性质与晶体结构提示的信息是一致的。以此模型提示的三维信息，本文共设计了六类选择性环氧合酶-2抑制剂，活性预测表明它们具有合成价值。目前，已合成了部分化合物，药理活性筛选正在进行之中。
(2)利用对接程序建立了结构差别较大的三环类，NS-398类抑制剂，及吲哚美辛同环氧合酶-2的结合能与抑制活性的相关方程。在建立该模型的同时，解释了NS-398类抑制剂虽然没有三环系化合物的中间桥连环，但是由于这类化合物的硝基与酶形成了氢键作用使得它们仍然具有较高的抑制活性。
(3)利用分子图形学用定量和定性的方法，阐明了环氧合酶-2和环氧合酶-1同相应的抑制剂选择性结合的原因。
(4)根据构象分析以及配体／受体复合物的三维结构，定义了药效团模型，对NCI-3D(National Cancer Institute，美国国家癌症研究所)和Maybridge-3D数据库进行三维结构搜索，共发现15个有可能具有COX-2选择性抑制活性的化合物，这些化合物结构信息的获得，为下一步的合成提供了新的结构骨架。
2．抗肿瘤药紫杉醇的三维定量构效关系研究
紫杉醇具有明显的抗肿瘤活性，目前己用于临床治疗乳腺癌和子宫癌。由于它的水溶性低且具有一些副作用等缺点，有关的紫杉醇的结构修饰仍在继续中。本文选择
Rational drug design is a critical step in pharmaceutical industry. The development of computer hardware and software make it possible to rationally design new drug with computer-aided drug design (CADD), CADD contribute not only to the design of potent compounds, but to many of the steps of going "from concept to clinic". In this thesis, we studied several projects by CADD as follows.
1. Structure-Based Design of Selective Cyclooxygenase-2 (COX-2) Inhibitors
The discovery of COX-2 provided a new target for the design of nonsteroidal anti-inflammatory Drugs (NSAIDs) with less side effects. In order to disclose the relationship between the activity and structure, the studies contained four aspects:
(1)A series of 44 selective COX-2 inhibitors were investigated with the aim of developing a 3D-QSAR model using the comparative molecular field analysis (CoMFA). The active conformation was extracted from the SC-558/COX-2 complex but the alignment of the molecule was performed through two approaches, one is atom to atom operation, the other is determined by DOCK. The model from DOCK alignment shows higher ability to explain and predict the activity of selective COX-2 inhibitor than the model from the classical atom to atom alignment. The feature of this 3D-model are consistent with the binding pocket. According to the model derived from DOCK-based CoMFA, six classes of inhibitors of COX-2 were designed, five of which have been synthesized and their activities assay are being tested.
(2)By using DOCK program, the relationship between activity and binding energy for tricycle inhibitors, NS-398 analogues and Indomethacin was constructed. In addition, DOCK mimics the binding of NS-398 analogues to COX-2, and the results indicated that NS-398 analogues possess higher activity because of the presence of additional hydrogen-bondings.
(3) In order to understand the specificity of COX-2 and COX-1, selective COX-2 and non-selective inhibitors were docked into COX-1 and COX-
引文
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