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【目的】通过分子模拟和活性测试筛选非核苷类抗人类免疫缺陷病毒-1(HIV-1)逆转录酶活性化合物。【方法】采用Tripos SYBYL软件Surflex-Dock分子对接模块,模拟SPECS数据库中22 000个化合物与HIV-1逆转录酶活性口袋的结合,根据模拟结果分析化合物与HIV-1逆转录酶晶体结构的相互作用模式。对于打分较高与结合模式较优的化合物,采用体外抗HIV-1活性测试方法检测其生物活性。【结果】虚拟筛选结果显示化合物1-(4-fluorophenyl)-3-[2-(1H-indol-3-yl)ethyl]thiourea对接构象与晶体结构中内嵌配体非常接近,它与HIV-1逆转录酶结合口袋重要残基Lys101形成氢键、与保守残基Trp229和芳香残基Tyr181分别形成π-π堆积作用。体外抗HIV-1活性测试结果显示其抑制HIV-1IIIB病毒感染的C8166淋巴细胞合胞体形成50%时的浓度即EC50值为5.45μg/m L。【结论】分子对接技术能缩小活性化合物筛选范围,并可用于预测化合物与蛋白质的相互作用模式,本研究利用该技术筛选出活性化合物。
【Objective】 To screen non-nucleoside anti-human immunodeficiency virus-1 (HIV-1) reverse transcriptase compounds by molecular simulation and bioassay. 【Method】 The Surflex-Dock molecular docking module of Tripos SYBYL software was used to simulate the binding of 22 000 compounds in the SPECS database to the active pocket of HIV-1 reverse transcriptase. The crystal structures of the compounds and HIV-1 reverse transcriptase were analyzed according to the simulation results Mode of action. For compounds with higher scoring and better binding mode, their biological activity was tested by in vitro anti-HIV-1 activity test. 【Result】 The results of the virtual screening showed that the docking conformation of the compound 1- (4-fluorophenyl) -3- [2- (1H-indol-3-yl) ethyl] thiourea is very close to that of the ligand in the crystal structure, 1 reverse transcriptase binds to the pocket critical Lys101 hydrogen bond, forming a π-π stacking interaction with the conserved residue Trp229 and the aromatic residue Tyr181, respectively. The results of in vitro anti-HIV-1 activity test showed that the concentration of EC50 of C8166 lymphocyte syncytia, which inhibits HIV-1 IIIB virus infection at 50%, was 5.45 μg / m L. 【Conclusion】 The molecular docking technology can reduce the screening range of active compounds and can be used to predict the interaction between the compounds and proteins. In this study, the active compounds were screened out.