天然产物研究与开发 ›› 2020, Vol. 32 ›› Issue (12): 1981-1991.doi: 10.16333/j.1001-6880.2020.12.001

所属专题: 新冠专题

• 专题研究 •    下一篇

基于处方挖掘与药效团模型的新型冠状病毒RdRp抑制成分筛选

李婧1,2,韦缤琪1,李可馨1,苏学燕1,3,张志锋1,3*   

  1. 1西南民族大学药学院;2四川大学生物治疗国家重点实验室,成都 610041;3四川省羌彝药用资源保护与利用技术工程实验室,成都 610225

  • 出版日期:2020-12-28 发布日期:2020-12-24
  • 基金资助:
    国家重点研发计划(2019YFC1712501);四川省科技厅应用基础项目(2020YJ0277);西南民族大学大学生创新创业训练计划(S202010656130)

Screening of RdRp inhibitors against SARS-CoV-2 based on prescription mining and pharmacophore

LI Jing1,2,WEI Bin-qi1,LI Ke-xin1,SU Xue-yan 1,3,ZHANG Zhi-feng1,3*   

  1. 1College of Pharmmacy,Southwest Minzu University;2State Key Laboratory of Biotherapy,Sichuan University,Chengdu 610041,China;
    3Sichuan Provincial Qiang-Yi Medicinal Resources Protection and Utilization Technology Engineering Laboratory,Chengdu 610225,China

  • Online:2020-12-28 Published:2020-12-24

摘要:

本研究采用药效团模型对作用于新型冠状病毒(SARS-CoV-2)RdRp靶点的常用中药成分进行筛选,寻找潜在活性成分。对临床常用抗新冠肺炎中药处方进行全面挖掘及筛选,分析统计常用药材及使用频数,利用中药系统药理学分析平台(TCMSP)及文献挖掘的方式筛选“抗新冠候选活性成分”,以已报道的具有RdRp酶抑制活性的化合物作为训练集,建立基于RdRp配体的HipHop 药效团模型,将候选成分与药效团进行匹配,采用分子对接技术对匹配到FitValue较高的化合物与SARS-CoV-2病毒RdRp蛋白进行对接并评估其相互作用。共搜集到临床常用中药处方31个,包含药材92种。通过TCMSP及文献挖掘得到药材中1 384种候选活性成分。通过测试集验证的最优药效团02具有1个氢键供体及2个氢键受体,与候选成分匹配得到104种潜在RdRp抑制活性成分。选取FitValue较高且结合自由能较低的前30种化合物进行分析,发现liquiritin apioside、iridin、liquiritin、forsythiaside、procyanidin B-5,3′-O-gallate及saikosaponin C等成分具有较高的FitValue,可作为RdRp抑制的潜在活性成分。通过分类分析发现黄酮类结构可能是抑制RdRp的潜在活性基团。本研究通过构建药效团模型对常用抗新冠中药处方中抑制SARS-CoV-2 RdRp潜在活性成分进行了虚拟筛选,希望对抗SARS-CoV-2活性成分筛选提供参考思路。

关键词: 新型冠状病毒疾病, SARS-CoV-2, RdRp抑制剂, 中药处方, 药效团, 分子对接

Abstract:

In order to screen the potential RdRp inhibitors against SARS-CoV-2 based on prescription mining and pharmacophore.A comprehensive mining and screening of commonly used prescriptions was conducted and the use frequency of Chinese herbal medicines was calculated.The active components were screened by Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and literature mining.RdRp ligand-based pharmacophore model was set up by collecting published literature.The constituents from candidate active ingredients were screened for the potential RdRp inhibitors through matching with the best pharmacophore model.Molecular docking was used to evaluate the interactions between potential active compounds and SARS-CoV-2 RdRp protein.A total of 31 prescriptions including 92 kinds of herbs were collected.One thousand three hundred and eighty-four compounds were collected by TCMSP and literature mining.The optimized pharmacophore model,which was validated by test set,contained one hydrogen bond donor and two hydrogen bond acceptor.One hundred and four potential RdRp inhibitory constituents from candidate active ingredients were matched with the optimized pharmacophore model.The top 30 compounds with higher FitValue and lower binding free energy were selected for the analysis.Liquiritin apioside,iridin,liquiritin,forsythiaside,procyanidin B-5,3′-O-gallate,and saikosaponin C showed higher FitValue and lower binding energy,which were considered as potential active compounds.Flavonoids may be the potential active structure of RdRp inhibitors.A pharmacophore model was constructed to screen the potential RdRp inhibitors from commonly used prescriptions,in order to provide some ideas for screening the active components against SARS-CoV-2.

Key words: novel coronavirus pneumonia, SARS-CoV-2, RdRp inhibitors, prescription of traditional Chinese Medicine, pharmacophore, molecular docking

中图分类号:  R932