基于分子对接技术筛选抗新型冠状病毒的先导化合物

Screening of anti-SARS-CoV-2 leading compounds based on molecular docking technology

目的以冠状病毒纤突蛋白(S蛋白)和血管紧张素转化酶2(ACE2)受体的结合蛋白为靶标,基于本课题组前期建立的“配伍-拼合”中药活性成分库,筛选具有抗新型冠状病毒(SARS-CoV-2)的小分子抑制剂。方法根据SARS-CoV-2的病毒学和感染机制,采用Q-Site Finder确定S蛋白和ACE2受体的结合蛋白结构模型上的活性位点,采用分子对接技术,对白桦脂酸类、薯蓣皂苷元类、甾醇类、鬼臼毒素类4类120种化合物开展潜在药物筛选研究,结合打分值以及相同结构母核的成分之间比较,获得并验证具有抗SARS-CoV-2潜在活性的先导化合物。结果以Q-Site Finder预测得到的活性位点作为本次分子对接的关键受体残基,白桦脂酸和薯蓣皂苷元母核具有较好的结合能力,打分值前3%的化合物为3β-O-乙酰化胆甾醇(-13.1 kcal·mol^(-1))、BH-11(-12.9 kcal·mol^(-1))、BH-12(-12.9 kcal·mol^(-1)),鬼臼毒素结构母核不适合开展相关研究,取结合能绝对值较高的化合物与冠状病毒主要蛋白酶(3CLpro)蛋白对接验证了上述结果。结论白桦脂酸和薯蓣皂苷元母核化合物以及3β-O-乙酰化胆甾醇、BH-11、BH-12具有潜在的抗SARS-CoV-2活性,为后续抗SARS-CoV-2新药研发提供参考。

Objective To screen the novel small-molecule inhibitors against novel coronavirus(SARS-CoV-2),the binding protein combined spike protein of coronavirus(S protein)with angiotensin converting enzyme 2(ACE2)receptor was selected as the targets,based on"compatibility-combination"-TCM-compound database constructed by our group.Methods According to the virological and infection mechanisms of SARS-CoV-2,Q-Site Finder was used to identify the active sites on structural model of the binding protein combined S protein with ACE2 receptor,and molecular docking technology was employed to conduct the potential drug screening research from 4 kinds of 120 compounds such as betulinic acids,diosgenins,sterols,and podophyllotoxins by comparing the score value between the components of the same structure parent nucleusy.Results The active sites predicted by Q-site Finder were used as the key receptor residues for this molecular docking,and the structure parent nucleus of betulinic acid and diosgenin showed preferable binding ability,with 3β-O-acetylated cholesterol(-13.1 kcal·mol^(-1)),BH-11(-12.9 kcal·mol^(-1))and BH-12(-12.9 kcal·mol^(-1))as the top 3%compounds.Meanwhile,the structural parent nucleus of podophyllotoxin was not suitable for relevant research.Above results were verified by docking compounds with the higher absolute value of binding ability with 3CLpro.Conclusion The structure parent nucleus of betulinic acid,diosgenin,as well as 3β-O-acetylated cholesterol,BH-11 and BH-12 have the potential anti-SARS-CoV-2 effect,which can provide references for the subsequent new drug research and development against SARS-CoV-2.