摘要
目的:以SARS-CoV-S/ACE2复合蛋白和严重急性呼吸综合征冠状病毒2(severe acute respiratory syndrome coronavirus 2,SARS-CoV-2) Mpro水解酶为靶标,从TCMSP数据库中筛选SARS-CoV-2-ACE2结合阻断剂和SARS-CoV-2 Mpro水解酶抑制剂,指导以中药小分子为前体的抗SARS-CoV-2新药的研发。方法:根据文献报道,确定SARS-CoV-S/ACE2复合蛋白和SARS-CoV-2 Mpro水解酶晶体结构模型上的活性位点,利用LibDock分子对接技术虚拟筛选TCMSP数据库中的小分子化合物,结合打分值以及化合物与靶蛋白受体的相互作用模式优化筛选结果,获得具有抗SARS-CoV-2潜在活性的中药小分子化合物。结果:确定SARS-CoV-S/ACE2复合蛋白结构中位于结合表面上的ASP38,GLN42,GLN325,GLU329,TYR436和TYR491以及SARS-CoV-2 Mpro水解酶结构中的THR24,THR25,THR26,LEU27,ASN28和ASN119为本次分子对接的关键氨基酸;分子对接筛选得到20个能与关键氨基酸形成氢键的候选SARS-CoV-2-ACE2结合阻断剂,其中主要来源于栀子、甘草、山豆根和洋金花的4个成分与靶蛋白的对接效果较好;筛选得到34个能与关键氨基酸形成氢键的候选SARS-CoV-2 Mpro水解酶抑制剂,其中主要来源于干姜、黄药子、升麻、荠菜的4个成分与靶蛋白的对接效果较好;甘草成分甘草酚E和黄药子成分延龄草苷元分别与靶蛋白作用的关键氨基酸数量最多或形成的氢键数量最多,分子对接效果最优。结论:来源于中药的4个SARS-CoV-2-ACE2结合阻断剂和4个SARS-CoV-2 Mpro水解酶抑制剂具有潜在的抗SARS-CoV-2活性,其中甘草成分甘草酚E和黄药子成分延龄草苷元可优先选择进行后续抗SARS-CoV-2新药的研发。
Objective: Based on the targets of SARS-CoV-S/ACE2 complex and SARS-CoV-2 Mpro hydrolase, we screened the binding blockers of SARS-CoV-2-ACE2 and inhibitors of SARS-CoV-2 Mpro hydrolase from TCMSP database as precursors to guide the discovery of new drugs from small molecules of traditional Chinese medicine(TCM) against SARS-CoV-2. Methods: According to the literature reports, the active sites of the crystal structure model of SARS-CoV-S/ACE2 complex protein and SARS-CoV-2 Mpro hydrolase were determined, and the small molecular compounds from TCMSP database were virtually screened using LibDock molecular docking technology. The screening results were optimized by combining the LibDock Score with the interaction mode between the compounds and the targeting receptor protein, and then the small molecular compounds of TCM which have the potential activity of anti-SARS-CoV-2 were obtained. Results: ASP38, GLN42, GLN325, GLU329, TYR436, TYR491 on the binding surface of SARS-CoV-S/ACE2 complex protein and THR24, THR25, THR26, LEU27, ASN28, ASN119 in the structure of Mpro hydrolase were identified as the key amino acids for molecular docking. Twenty candidate SARS-CoV-2-ACE2 binding blockers which can form hydrogen bond with key amino acids were screened by molecular docking, and the docking effect of four components mainly from Gardeniae Fructus, Glycyrrhizae Radix Et Rhizoma, Sophorae Tonkinensis Radix Et Rhizoma and Daturae Flos with the targeting protein was better than others. Thirty-four candidate SARS-CoV-2 Mpro hydrolase inhibitors which can form hydrogen bond with key amino acids were also screened, and the docking effect of four components mainly from Zingiberis Rhizoma, Rhizoma Dioscoreae Bulbiferae, Cimicifugae Rhizoma and Capsella Bursa-pastoris with the targeting protein was better than others. Kanzonol E from Glycyrrhizae Radix Et Rhizoma and kryptogenin from Rhizoma Dioscoreae Bulbiferae could interact with the largest number of key amino acids or form the most hydrogen bonds with the targeting protein respectively, and had the best molecular docking effect. Conclusion: Four candidate SARS-CoV-2-ACE2 binding blockers and four candidate SARS-CoV-2 Mpro hydrolase inhibitors from TCM have the potential activity of anti-SARS-CoV-2, among which priority can be given to kanzonol E, a component of Glycyrrhizae Radix Et Rhizoma, and kryptogenin, a component of Rhizoma Dioscoreae Bulbiferae, for further discovery of anti-SARS-CoV-2 new drugs.
作者
沈亮亮
李勇
周明
谯英固
孙震晓
SHEN Liang-liang;LI Yong;ZHOU Ming;QIAO Ying-gu;SUN Zhen-xiao(School of Life Sciences,Beijing University of Chinese Medicine,Beijing 102488,China)
出处
《中国新药杂志》
CAS
CSCD
北大核心
2020年第7期773-781,共9页
Chinese Journal of New Drugs
基金
北京中医药大学2019年研究生自主课题资助项目(2019-JYB-XS-112)
关键词
分子对接
SARS-CoV-2
虚拟筛选
中药小分子化合物
新药研发
molecular docking
SARS-CoV-2
virtual screening
small molecular compounds of traditional Chinese medicine
new drug discovery
