基于分子对接的HIV-1 RT抑制剂虚拟筛选的方法
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摘要
在1型艾滋病病毒(HIV-1)药物筛选过程中,将已发现的高效非核苷类反转录酶抑制剂作为先导化合物进行药物设计,利用分子动力学、分子对接、定量构效关系等手段分析和筛选,再采用生物实验验证的方法,可以克服仅仅依赖于数据库进行大面积盲目筛选而导致的低效率,低阳性的缺点。这为非核苷类反转录酶抑制剂的进一步研究和发展提供了有利的基础。通过研究发现,在腙衍生物、吲哚酮类、嘧啶羧酸类、二芳基三嗪类、富勒烯衍生物等多类化合物中均发现了具有微摩尔级的抑制HIV活性的物质。有些药物也已经经实验验证具有微摩尔级的抗核糖核酸酶H的活性,并能够对以往药物无法作用的RT酶突变株产生明显的抑制作用。本文对基于数据库,从既往研究中得到初始化合物和设计衍生物三个方面的筛选方法进行综述。
In the screening process of HIV-1 inhibitors, the high-efficient non-nucleoside reverse transcriptase inhibitors,known as the lead compound, are used for further analysis by these methods, like molecular dynamics, molecular docking, QSAR, and then biological experiments are used to validate their activity. These methods can overcome the shortcomings of inefficiency and low positivity caused by solely relying on large-scale blind screening of databases. This provides a favorable basis for further research and development on non-nucleoside reverse transcriptase inhibitors. Micromole-level inhibitor against HIV activity has been found in various compounds such as hydrazone derivatives, indolones, pyrimidinecarboxylic acids, diaryltriazines and fullerene derivatives. Also, some inhibitors have been experimentally demonstrated to have the activity of micromole-level anti-RNase H, and a significantly inhibitory effect on the RT enzyme mutants that are effective to previous inhibitors. This paper reviews the three methods of screening methods based on database, previous studies, and screening methods for designing derivatives.
In the screening process of HIV-1 inhibitors, the high-efficient non-nucleoside reverse transcriptase inhibitors,known as the lead compound, are used for further analysis by these methods, like molecular dynamics, molecular docking, QSAR, and then biological experiments are used to validate their activity. These methods can overcome the shortcomings of inefficiency and low positivity caused by solely relying on large-scale blind screening of databases. This provides a favorable basis for further research and development on non-nucleoside reverse transcriptase inhibitors. Micromole-level inhibitor against HIV activity has been found in various compounds such as hydrazone derivatives, indolones, pyrimidinecarboxylic acids, diaryltriazines and fullerene derivatives. Also, some inhibitors have been experimentally demonstrated to have the activity of micromole-level anti-RNase H, and a significantly inhibitory effect on the RT enzyme mutants that are effective to previous inhibitors. This paper reviews the three methods of screening methods based on database, previous studies, and screening methods for designing derivatives.
引文
[1] Gupta RK, Gregson J, Parkin N, et al. HIV-1 drug resistance before initiation or re-initiation of first-line antiretroviral therapy in low-income and middle-income countries: a systematic review and meta-regression analysis[J]. Lancrt Infect Dis, 2017, 18(3):346-355.
[2] Finley J. Reactivation of latently infected HIV-1 viral reservoirs and correction of aberrant alternative splicing in the LMNA gene via AMPK activation: Common mechanism of action linking HIV-1 latency and Hutchinson-Gilford progeria syndrome[J]. Med Hypotheses, 2015, 85(3): 320-332.
[3] Padariya M, Kalathiya U, Baginski M. Molecular basis and potential activity of HIV-1 reverse transcriptase towards triethylamine based compounds[J]. Appl Biochem Biotech, 2017, 64(6): 810-826.
[4] Lapkouski M, Lan T, Miller JT, et al. Complexes of HIV-1 RT, NNRTI and RNA/DNA hybrid reveal a structure compatible with RNA degradation[J]. Nat Struct Mol Biol, 2013, 20(2): 230.
[5] 孟欢欢, 顾良凤. 分子对接及其在药物设计中的作用综述[J]. 家庭心理医生, 2014(12):194-194.
[6] 陈芳玲, 李向前, 江涛,等. 抗肿瘤蛋白数据库的建立及其在海洋小分子化合物反向寻靶中的应用[J]. 中国海洋药物, 2017, 36(2):1-6.
[7] 张海玲, 光翠娥, 江波, 等. 皂苷类似物与肾素的分子对接和结合能分析[J]. 食品与生物技术学报, 2014, 33(10): 1056-1062.
[8] 赵晨, 夏春光, 于敏, 等. 分子对接软件在药物设计中的应用[J]. 中国抗生素杂志, 2015, 40(3): 234-240.
[9] 冀树伸, 黄新安, 罗荣华, 等. 分子对接技术筛选抗HIV-1逆转录酶活性化合物[J]. 广州中医药大学学报, 2015, 4(4): 725-728.
[10] Distinto S, Esposito F, Kirchmair J, et al. Identification of HIV-1 reverse transcriptase dual inhibitors by a combined shape-, 2D-fingerprint-and pharmacophore-based virtual screening approach[J]. Eur J Med Chem, 2012, 50(50): 216-229.
[11] Grohmann D, Corradi V, Elbasyouny M, et al. Small molecule inhibitors targeting HIV-1 reverse transcriptase dimerization[J]. Chembiochem, 2008, 9(6): 916-922.
[12] Tintori C, Corona A, Esposito F, et al. Inhibition of HIV-1 Reverse Transcriptase Dimerization by Small Molecules[J]. Chembiochem, 2016, 17(8): 683-688.
[13] 邓联柏, 李爱秀, 靳玉瑞, 等. 运用计算模拟技术揭示黄芩素抗HIV的新机制[J]. 武警后勤学院学报(医学版), 2013, (9): 753-755.
[14] 张洁, 谭初兵, 徐为人. Lipinski五规则的研究进展[J]. 药物评价研究, 2011, 34(6): 451-455.
[15] Xiong YZ, Chen FE, Balzarini J, et al. Non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 11: structural modulations of diaryltriazines with potent anti-HIV activity[J]. Eur J Med Chem, 2008, 43(6): 1230-1236.
[16] Xiong YZ, Chen FE, Balzarini J, et al. Non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 13: synthesis of fluorine-containing diaryltriazine derivatives for in vitro anti-HIV evaluation against wild-type strain[J]. Chem Biodivers, 2009, 6(4): 561-568.
[17] 王琴, 梅虎, 孙家英, 等. 二芳基三嗪类HIV-1逆转录酶抑制剂的分子对接及3D-QSAR研究[J]. 化学通报, 2011, 74(1): 54-60.
[18] Viira B, Selyutina A, García-sosa AT, et al. Design, discovery, modelling, synthesis, and biological evaluation of novel and small, low toxicity s-triazine derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors[J]. Bioorg Med Chem, 2016, 24(11): 2519-2529.
[19] 周丹丹, 于延庆, 吴昊, 等. 分子伴侣HdeA与底物蛋白SurA作用机制的模拟研究[J]. 生物化学与生物物理进展, 2017, 44(3):242-252.
[20] C?té B, Burch JD, Asanteappiah E, et al. Discovery of MK-1439, an orally bioavailable non-nucleoside reverse transcriptase inhibitor potent against a wide range of resistant mutant HIV viruses[J]. Bioorg Med Chem Lett, 2014, 24(3): 917-922.
[21] Hosseini Y, Mollica A, Mirzaie S. Structure-based virtual screening efforts against HIV-1 reverse transcriptase to introduce the new potent non-nucleoside reverse transcriptase inhibitor[J]. J Mol Struct, 2016(1125): 592-600.
[22] Luo PH, Zhang XR, Huang L, et al. 3D-QSAR pharmacophore-based virtual screening, molecular docking and molecular dynamics simulation toward identifying lead compounds for NS2B-NS3 protease inhibitors[J]. J Recept Signal Transduct Res, 2017, 37(5): 481-492.
[23] Nakamura S, Mashino T. Biological activities of water-soluble fullerene derivatives[C]. J Phys Conf Ser, 2009, 159(1): 012003.
[24] Yilmaz H, Ahmed L, Rasulev B, et al. Application of ligand-and receptor-based approaches for prediction of the HIV-RT inhibitory activity of fullerene derivatives[J]. J Nanopart Res, 2016, 18(5): 1-12.
[25] Su DS, Lim JE. Substituted tetrahydroquinolines as potent allosteric inhibitors of reverse transcriptase and its key mutants[J]. Bioorg Med Chem Lett, 2009, 19(17): 5119-5123.
[26] Zhang J, Zhan P, Wu J, et al. Synthesis and biological evaluation of novel 5-alkyl-2-arylthio-6-((3,4-dihydroquinolin-1(2 H)-yl)methyl)pyrimidin-4(3 H)-ones as potent non-nucleoside HIV-1 reverse transcriptase inhibitors[J]. Bioorg Med Chem, 2011, 19(14): 4366-4376.
[27] Chander S, Wang P, Ashok P, et al. Rational design, synthesis, anti-HIV-1 RT and antimicrobial activity of novel 3-(6-methoxy-3,4-dihydroquinolin-1(2 H)-yl)-1-(piperazin-1-yl)propan-1-one derivatives[J]. Bioorg Chem, 2016, 67(1): 75-83.
[28] 乔恒. DAPY类HIV-1抑制剂的设计、合成与抗HIV活性研究[D]. 武汉:武汉工程大学, 2015.
[29] Mark Cushman , Agustin Casimirogarcia, Elzbieta Hejchman, et al. New Alkenyldiarylmethanes with Enhanced Potencies as Anti-HIV Agents Which Act as Non-Nucleoside Reverse Transcriptase Inhibitors[J]. J Med Chem, 1998, 41(12): 2076-2089.
[30] Silvestri R, Artico M, Massa S, et al. ChemInform Abstract: 1-[2- (Diphenylmethoxy)ethyl]-2-methyl-5-nitroimidazole: A Potent Lead for the Design of Novel NNRTIs[J]. Bioorg Med Chem Lett, 2000, 10(3): 253-256.
[31] Kennedysmith JJ, Arora N, Billedeau JR, et al. Synthesis and biological activity of new pyridonediaryl ether non-nucleoside inhibitors of HIV-1 reverse transcriptase[J]. Med. Chem. Commun., 2010, 1(1): 79-83.
[32] Chander S, Wang P, Ashok P, et al. Design, synthesis and anti-HIV-1 RT evaluation of 2-(benzyl(4-chlorophenyl)amino)-1-(piperazin-1-yl)ethanone derivatives[J]. Bioorg Med Chem Lett, 2016, 1(27): 61-65.
[33] Alogheli H, Olanders G, Schaal W, et al. Docking of Macrocycles: Comparing Rigid and Flexible Docking in Glide[J]. J Chem Inf Model, 2017, 57(2): 190-202.
[34] Hm K, Sc J, Sr B. Synthesis and molecular docking studies of oxochromenyl xanthenone and indolyl xanthenone derivatives as anti-HIV-1 RT inhibitors[J]. Bioorg Med Chem Lett, 2015, 25(18): 3882-3886.
[35] Himmel DM, Myshakina NS, Ilina T, et al. Structure of a dihydroxycoumarin active-site inhibitor in complex with the RNase H domain of HIV-1 reverse transcriptase and structure-activity analysis of inhibitor analogs[J]. J Mol Biol, 2014, 426(14): 2617-2631.
[36] Dominga R, Alessia B, Laura DL, et al. Investigation of the salicylaldehyde thiosemicarbazone scaffold for inhibition of influenza virus PA endonuclease[J]. J Biol Inorg Chem, 2015, 20(7): 1109-1121.
[37] Rogolino D, Carcelli M, Bacchi A, et al. A versatile salicyl hydrazonic ligand and its metal complexes as antiviral agents[J]. J Inorg Biochem, 2015(150): 9-17.
[38] Sechi M, Innocenti A, Pala N, et al. Inhibition of α-class cytosolic human carbonic anhydrases I, II, IX and XII, and β-class fungal enzymes by carboxylic acids and their derivatives: New isoform-I selective nanomolar inhibitors[J]. Bioorg Med Chem Lett, 2012, 22(18): 5801-5806.
[39] Pala N, Esposito F, Rogolino D, et al.Inhibitory Effect of 2,3,5,6-Tetrafluoro-4-[4-(aryl)-1H-1,2,3-triazol-1-yl] benzenesulfonamide Derivatives on HIV Reverse Transcriptase Associated RNase H Activities[J].Int J Mol Sci, 2016, 17(8):1371-1384.
[2] Finley J. Reactivation of latently infected HIV-1 viral reservoirs and correction of aberrant alternative splicing in the LMNA gene via AMPK activation: Common mechanism of action linking HIV-1 latency and Hutchinson-Gilford progeria syndrome[J]. Med Hypotheses, 2015, 85(3): 320-332.
[3] Padariya M, Kalathiya U, Baginski M. Molecular basis and potential activity of HIV-1 reverse transcriptase towards triethylamine based compounds[J]. Appl Biochem Biotech, 2017, 64(6): 810-826.
[4] Lapkouski M, Lan T, Miller JT, et al. Complexes of HIV-1 RT, NNRTI and RNA/DNA hybrid reveal a structure compatible with RNA degradation[J]. Nat Struct Mol Biol, 2013, 20(2): 230.
[5] 孟欢欢, 顾良凤. 分子对接及其在药物设计中的作用综述[J]. 家庭心理医生, 2014(12):194-194.
[6] 陈芳玲, 李向前, 江涛,等. 抗肿瘤蛋白数据库的建立及其在海洋小分子化合物反向寻靶中的应用[J]. 中国海洋药物, 2017, 36(2):1-6.
[7] 张海玲, 光翠娥, 江波, 等. 皂苷类似物与肾素的分子对接和结合能分析[J]. 食品与生物技术学报, 2014, 33(10): 1056-1062.
[8] 赵晨, 夏春光, 于敏, 等. 分子对接软件在药物设计中的应用[J]. 中国抗生素杂志, 2015, 40(3): 234-240.
[9] 冀树伸, 黄新安, 罗荣华, 等. 分子对接技术筛选抗HIV-1逆转录酶活性化合物[J]. 广州中医药大学学报, 2015, 4(4): 725-728.
[10] Distinto S, Esposito F, Kirchmair J, et al. Identification of HIV-1 reverse transcriptase dual inhibitors by a combined shape-, 2D-fingerprint-and pharmacophore-based virtual screening approach[J]. Eur J Med Chem, 2012, 50(50): 216-229.
[11] Grohmann D, Corradi V, Elbasyouny M, et al. Small molecule inhibitors targeting HIV-1 reverse transcriptase dimerization[J]. Chembiochem, 2008, 9(6): 916-922.
[12] Tintori C, Corona A, Esposito F, et al. Inhibition of HIV-1 Reverse Transcriptase Dimerization by Small Molecules[J]. Chembiochem, 2016, 17(8): 683-688.
[13] 邓联柏, 李爱秀, 靳玉瑞, 等. 运用计算模拟技术揭示黄芩素抗HIV的新机制[J]. 武警后勤学院学报(医学版), 2013, (9): 753-755.
[14] 张洁, 谭初兵, 徐为人. Lipinski五规则的研究进展[J]. 药物评价研究, 2011, 34(6): 451-455.
[15] Xiong YZ, Chen FE, Balzarini J, et al. Non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 11: structural modulations of diaryltriazines with potent anti-HIV activity[J]. Eur J Med Chem, 2008, 43(6): 1230-1236.
[16] Xiong YZ, Chen FE, Balzarini J, et al. Non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 13: synthesis of fluorine-containing diaryltriazine derivatives for in vitro anti-HIV evaluation against wild-type strain[J]. Chem Biodivers, 2009, 6(4): 561-568.
[17] 王琴, 梅虎, 孙家英, 等. 二芳基三嗪类HIV-1逆转录酶抑制剂的分子对接及3D-QSAR研究[J]. 化学通报, 2011, 74(1): 54-60.
[18] Viira B, Selyutina A, García-sosa AT, et al. Design, discovery, modelling, synthesis, and biological evaluation of novel and small, low toxicity s-triazine derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors[J]. Bioorg Med Chem, 2016, 24(11): 2519-2529.
[19] 周丹丹, 于延庆, 吴昊, 等. 分子伴侣HdeA与底物蛋白SurA作用机制的模拟研究[J]. 生物化学与生物物理进展, 2017, 44(3):242-252.
[20] C?té B, Burch JD, Asanteappiah E, et al. Discovery of MK-1439, an orally bioavailable non-nucleoside reverse transcriptase inhibitor potent against a wide range of resistant mutant HIV viruses[J]. Bioorg Med Chem Lett, 2014, 24(3): 917-922.
[21] Hosseini Y, Mollica A, Mirzaie S. Structure-based virtual screening efforts against HIV-1 reverse transcriptase to introduce the new potent non-nucleoside reverse transcriptase inhibitor[J]. J Mol Struct, 2016(1125): 592-600.
[22] Luo PH, Zhang XR, Huang L, et al. 3D-QSAR pharmacophore-based virtual screening, molecular docking and molecular dynamics simulation toward identifying lead compounds for NS2B-NS3 protease inhibitors[J]. J Recept Signal Transduct Res, 2017, 37(5): 481-492.
[23] Nakamura S, Mashino T. Biological activities of water-soluble fullerene derivatives[C]. J Phys Conf Ser, 2009, 159(1): 012003.
[24] Yilmaz H, Ahmed L, Rasulev B, et al. Application of ligand-and receptor-based approaches for prediction of the HIV-RT inhibitory activity of fullerene derivatives[J]. J Nanopart Res, 2016, 18(5): 1-12.
[25] Su DS, Lim JE. Substituted tetrahydroquinolines as potent allosteric inhibitors of reverse transcriptase and its key mutants[J]. Bioorg Med Chem Lett, 2009, 19(17): 5119-5123.
[26] Zhang J, Zhan P, Wu J, et al. Synthesis and biological evaluation of novel 5-alkyl-2-arylthio-6-((3,4-dihydroquinolin-1(2 H)-yl)methyl)pyrimidin-4(3 H)-ones as potent non-nucleoside HIV-1 reverse transcriptase inhibitors[J]. Bioorg Med Chem, 2011, 19(14): 4366-4376.
[27] Chander S, Wang P, Ashok P, et al. Rational design, synthesis, anti-HIV-1 RT and antimicrobial activity of novel 3-(6-methoxy-3,4-dihydroquinolin-1(2 H)-yl)-1-(piperazin-1-yl)propan-1-one derivatives[J]. Bioorg Chem, 2016, 67(1): 75-83.
[28] 乔恒. DAPY类HIV-1抑制剂的设计、合成与抗HIV活性研究[D]. 武汉:武汉工程大学, 2015.
[29] Mark Cushman , Agustin Casimirogarcia, Elzbieta Hejchman, et al. New Alkenyldiarylmethanes with Enhanced Potencies as Anti-HIV Agents Which Act as Non-Nucleoside Reverse Transcriptase Inhibitors[J]. J Med Chem, 1998, 41(12): 2076-2089.
[30] Silvestri R, Artico M, Massa S, et al. ChemInform Abstract: 1-[2- (Diphenylmethoxy)ethyl]-2-methyl-5-nitroimidazole: A Potent Lead for the Design of Novel NNRTIs[J]. Bioorg Med Chem Lett, 2000, 10(3): 253-256.
[31] Kennedysmith JJ, Arora N, Billedeau JR, et al. Synthesis and biological activity of new pyridonediaryl ether non-nucleoside inhibitors of HIV-1 reverse transcriptase[J]. Med. Chem. Commun., 2010, 1(1): 79-83.
[32] Chander S, Wang P, Ashok P, et al. Design, synthesis and anti-HIV-1 RT evaluation of 2-(benzyl(4-chlorophenyl)amino)-1-(piperazin-1-yl)ethanone derivatives[J]. Bioorg Med Chem Lett, 2016, 1(27): 61-65.
[33] Alogheli H, Olanders G, Schaal W, et al. Docking of Macrocycles: Comparing Rigid and Flexible Docking in Glide[J]. J Chem Inf Model, 2017, 57(2): 190-202.
[34] Hm K, Sc J, Sr B. Synthesis and molecular docking studies of oxochromenyl xanthenone and indolyl xanthenone derivatives as anti-HIV-1 RT inhibitors[J]. Bioorg Med Chem Lett, 2015, 25(18): 3882-3886.
[35] Himmel DM, Myshakina NS, Ilina T, et al. Structure of a dihydroxycoumarin active-site inhibitor in complex with the RNase H domain of HIV-1 reverse transcriptase and structure-activity analysis of inhibitor analogs[J]. J Mol Biol, 2014, 426(14): 2617-2631.
[36] Dominga R, Alessia B, Laura DL, et al. Investigation of the salicylaldehyde thiosemicarbazone scaffold for inhibition of influenza virus PA endonuclease[J]. J Biol Inorg Chem, 2015, 20(7): 1109-1121.
[37] Rogolino D, Carcelli M, Bacchi A, et al. A versatile salicyl hydrazonic ligand and its metal complexes as antiviral agents[J]. J Inorg Biochem, 2015(150): 9-17.
[38] Sechi M, Innocenti A, Pala N, et al. Inhibition of α-class cytosolic human carbonic anhydrases I, II, IX and XII, and β-class fungal enzymes by carboxylic acids and their derivatives: New isoform-I selective nanomolar inhibitors[J]. Bioorg Med Chem Lett, 2012, 22(18): 5801-5806.
[39] Pala N, Esposito F, Rogolino D, et al.Inhibitory Effect of 2,3,5,6-Tetrafluoro-4-[4-(aryl)-1H-1,2,3-triazol-1-yl] benzenesulfonamide Derivatives on HIV Reverse Transcriptase Associated RNase H Activities[J].Int J Mol Sci, 2016, 17(8):1371-1384.