基于药物靶点从传统中药库中高通量虚拟筛选HIV-1整合酶抑制剂

目的:运用虚拟筛选技术从传统中药数据库(traditional Chinese medicine database platform,TCMSP)中寻找HIV-1整合酶的中药小分子抑制剂。方法:以整合酶与细胞因子LEDGF/P75相互作用位点为靶点,运用分子对接技术进行首轮筛选,然后运用ADME/T预测进行第二轮筛选,最后基于靶点与药物相互作用位点进行第三轮筛选。结果:以原配体(4-[(5-bromo-4-{[2,4-dioxo-3-(2-oxo-2-phenylethyl)-1,3-thiazolidin-5-ylidene]methyl}-2-ethoxyphenoxy)-methyl]-benzoic acid,D77)为阳性对照,筛选出2个类药性良好的天然小分子化合物,二者与HIV-1整合酶亲和力及相互作用基团均优于D77(新型的HIV-1整合酶抑制剂),并且确定了它们的中草药来源。结论:成功建立一整套高通量虚拟筛选HIV-1整合酶抑制剂的策略,该研究结果可促进从传统中药库中提取、设计以及实验合成新的抗艾滋病药物。

High-flux Virtual Screening of HIV-1 Intergrase Inhibitors from TCMSP Based on Drug Target

Objective: To search small molecule inhibitors for HIV-1 intergrase from traditional Chinese medicine database platform (TCMSP) by using the virtual screening technology. Method: The interacting site between HIV-1 intergrase andcytokineLEDGF/P75 were taken as target. The molecular docking technology was used for the first round of screening, then the ADME/T prediction was adopted for the second round of screening, and finally the target point andthe interacting site were based for the third round of screening. Result: The free binding energy of original ligand (4-[(5-bromo-4-{[2,4-dioxo-3-(2-oxo-2-phenylethyl)-1,3-thiazolidin-5-ylidene]methyl}-2-ethoxyphenoxy)-methyl]-benzoic acid, D77) was be used as positive control to screen out two natural micro-molecule compounds with good drug likeness. Thenatural micro-molecule compounds, HIV-1 intergraseandinteractive perssad showed a superioraffinity to D77 (a new-typeintergrase inhibitor). Their sources of traditional Chinese medicine were determined. Conclusion: This study successfully established a high-throughput virtual screening strategy for HIV-1 intergrase inhibitors, and provides an important reference and theoretical basis for the extraction of anti-AIDS compounds from Chinese herbal medicine and the design of anti-AIDS drugs.