中药化学数据库中HIVRT(NNRTI)/IN双靶点抑制剂的虚拟筛选
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摘要
[目的]从天然产物中筛选人类免疫缺陷病毒(HIV)非核苷类逆转录酶抑制剂(NNRTI)和整合酶链转移抑制剂(INSTI)作用位点的双靶点抑制剂[RT(NNRTI)/IN]。[方法]运用分子模拟技术和计算机辅助药物设计(CADD)方法,构建HIV RT(NNRTI)/IN双靶点抑制剂分子相似性搜索模型、NNRTI和RT以及INSTI和IN对接模型,采用两种策略对中药化学数据库(TCMD)进行筛选。[结果]共命中与RT和IN对接得分均大于6的化合物35个,包括黄酮类、生物碱类、苷类、多酚类等,黄酮类化合物(15个)占到了42.86%。[结论]黄酮类化合物是开发潜在HIV RT(NNRTI)/IN双靶点抑制剂的主要来源,上述研究为天然产物来源的HIV双靶点药物发现提供了新线索。
[Objective] To find double target inhibitor of RT(NNRTI)/IN against HIV from natural products. [Methods] Molecular simulation and CADD technologies were used to build molecular similarity search model of double target inhibitor of RT(NNRTI)/IN against HIV, docking model of NNRTI and RT, docking model of INSTI and IN. Two strategies were used to screen Traditional Chinese Medicine Database(TCMD). [Results] The 35 molecules which docking scores with RT and IN were both above 6 were hit. There were flavonoids, alkaloids, glycosides, polyphenols, etc. Flavonoids(15) accounted for 42.86%. [Conclusion] Flavonoids are the main sources for the development of potential double target inhibitor of RT(NNRTI)/IN against HIV. These results provide new clues for the study of the dual target drugs of HIV derived from natural products.
[Objective] To find double target inhibitor of RT(NNRTI)/IN against HIV from natural products. [Methods] Molecular simulation and CADD technologies were used to build molecular similarity search model of double target inhibitor of RT(NNRTI)/IN against HIV, docking model of NNRTI and RT, docking model of INSTI and IN. Two strategies were used to screen Traditional Chinese Medicine Database(TCMD). [Results] The 35 molecules which docking scores with RT and IN were both above 6 were hit. There were flavonoids, alkaloids, glycosides, polyphenols, etc. Flavonoids(15) accounted for 42.86%. [Conclusion] Flavonoids are the main sources for the development of potential double target inhibitor of RT(NNRTI)/IN against HIV. These results provide new clues for the study of the dual target drugs of HIV derived from natural products.
引文
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[20]Liu DY,Ye JT,Yang WH,et al.Ampelopsin,a small molecule inhibitor of HIV-1 infection targeting HIV entry[J].Biomedical and Environmental Sciences,2004,17(2):153-164.
[2]李爱秀.多靶点药物的研究及筛选策略的提出[J].武警后勤学院学报:医学版,2013,22(11):1030-1034.
[3]展鹏,刘新泳,李潇,等.抗艾滋病药物设计新策略:多靶点及多价态结合配体[J].中国药物化学杂志,2013,23(5):406-416.
[4]李凯,李爱秀,靳玉瑞,等.天然产物来源的抗HIV-1多靶点抑制剂研究进展[J].中草药,2015,46(12):1840-1848.
[5]叶德泳.药物设计学[M].北京:高等教育出版社,2015:8.
[6]Tang J,Maddali K,Dreis CD,et al.6-Benzoyl-3-hydroxypyrimidine-2,4-diones as Dual Inhibitors of HIV Reverse Transcriptase and Integrase[J].Bioorganic&Medicinal Chemistry Letters,2011,21(8):2400-2402.
[7]Tang J,Maddali K,Dreis CD,et al.N-3 nydroxylation of pyrimidine-2,4-diones yields dual inhibitors of HIV reverse transcriptase and integrase[J].Acs Medicinal Chemistry Letters,2011,2(1):63-67.
[8]Islam MA,Pillay TS.Exploration of the structural requirements of HIV-protease inhibitors using pharmacophore,virtual screening and molecular docking approaches for lead identification[J].Journal of Molecular Graphics&Modelling,2015,56(2):20-30.
[9]Wu KZ,Li AX,Liu XT,et al.Building the pharmacophore model of HIV-1 integrase strand transfer inhibitors and studying their inhibition mechanism[J].Chinese Journal of Chemistry,2010,29(4):575-581.
[10]肖泽云,李凯,李爱秀,等.新型HIV逆转录酶和整合酶双靶点抑制剂的虚拟筛选[J].中国医药导报,2017,14(27):4-7.
[11]周家驹,谢桂荣,严新建.中药原植物化学成分手册[M].北京:化学工业出版社,2004:9.
[12]朱瑞新.计算机辅助药物设计:基本方法原理概要与实践详解[M].大连:大连理工大学出版社,2011.
[13]Belekar V,Shah A,Garg P.High-throughput virtual screening of phloroglucinol derivatives against HIV-reverse transcriptase[J].Molecular Diversity,2013,17(1):97-110.
[14]Ren J,Nichols C,Bird L,et al.Structural mechanisms of drug resistance for mutations at codons 181 and 188 in HIV-1 reverse transcriptase and the improved resilience of second generation nonnucleoside inhibitors[J].Journal of Molecular Biology,2001,312(4):795-805.
[15]吴可柱,李爱秀,缪有盼,等.HIV-1整合酶四聚体结构模拟及其活性位点分析[J].中国生物化学与分子生物学报,2009,25(6):549-555.
[16]孟歌,陈芬儿.HEPT类HIV-1逆转录酶抑制剂的研究进展[J].中国药物化学杂志,2004,14(1):56-64.
[17]Distinto S,Esposito F,Kirchmair J,et al.Identification of HIV-1reverse transcriptase dual inhibitors by a combined shape-,2Dfingerprint-and pharmacophore-based virtual screening approach[J].European Journal of Medicinal Chemistry,2012,50(50):216-229.
[18]吕琳,孙燕荣,徐伟,等.杜仲提取物抗HIV活性成分的分离鉴定[J].中药材,2008,31(6):847-850.
[19]Woo ER,Hwak JH,Kim HJ,et al.A new prenylated flavonol from the roots of Sophora flavescens[J].Journal of Natural Products,1998,61(12):1552-1554.
[20]Liu DY,Ye JT,Yang WH,et al.Ampelopsin,a small molecule inhibitor of HIV-1 infection targeting HIV entry[J].Biomedical and Environmental Sciences,2004,17(2):153-164.