Identify potent SARS-CoV-2 main protease inhibitors via accelerated free energy perturbation-based virtual screening of existing drugs

doi:10.1073/pnas.2010470117

	Identify potent SARS-CoV-2 main protease inhibitors via accelerated free energy perturbation-based virtual screening of existing drugs
	Li, Zhe 3; Li, Xin 4,5; Huang, Yi-You 3; Wu, Yaoxing 6; Liu, Runduo 3; Zhou, Lingli 6; Lin, Yuxi 4,5; Wu, Deyan 3; Zhang, Lei 6; Liu, Hao 7
刊名	PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
	2020-11-03
卷号	117 期号:44 页码:27381-27387
关键词	virtual screening SARS-CoV-2 drug repurposing free energy perturbation main protease
ISSN号	0027-8424
DOI	10.1073/pnas.2010470117
通讯作者	Cui, Jun(cuij5@mail.sysu.edu.cn) ; Zhan, Chang-Guo(zhan@uky.edu) ; Wang, Xin(wx8399@ouc.edu.cn) ; Luo, Hai-Bin(luohb77@mail.sysu.edu.cn)
英文摘要	The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global crisis. There is no therapeutic treatment specific for COVID-19. It is highly desirable to identify potential antiviral agents against SARS-CoV-2 from existing drugs available for other diseases and thus repurpose them for treatment of COVID-19. In general, a drug repurposing effort for treatment of a new disease, such as COVID-19, usually starts from a virtual screening of existing drugs, followed by experimental validation, but the actual hit rate is generally rather low with traditional computational methods. Here we report a virtual screening approach with accelerated free energy perturbation-based absolute binding free energy (FEP-ABFE) predictions and its use in identifying drugs targeting SARS-CoV-2 main protease (M-pro). The accurate FEP-ABFE predictions were based on the use of a restraint energy distribution (RED) function, making the practical FEP-ABFE-based virtual screening of the existing drug library possible. As a result, out of 25 drugs predicted, 15 were confirmed as potent inhibitors of SARS-CoV-2 M-pro. The most potent one is dipyridamole (inhibitory constant K-i = 0.04 mu M) which has shown promising therapeutic effects in subsequently conducted clinical studies for treatment of patients with COVID-19. Additionally, hydroxychloroquine (K-i = 0.36 mu M) and chloroquine (K-i = 0.56 mu M) were also found to potently inhibit SARS-CoV-2 M-pro. We anticipate that the FEP-ABFE prediction-based virtual screening approach will be useful in many other drug repurposing or discovery efforts.
资助项目	National Key R&D Program of China[2017YFB0202600] ; National Natural Science Foundation of China[81903542] ; National Natural Science Foundation of China[81522041] ; National Natural Science Foundation of China[21877134] ; Science Foundation of Guangdong Province[2020A111128007] ; Science Foundation of Guangdong Province[2018A030313215] ; Science Foundation of Guangdong Province[201904020023] ; Guangdong Provincial Key Laboratory of Construction Foundation[2017B030314030] ; Fundamental Research Funds for the Central Universities (Sun Yat-Sen University)[18ykpy23] ; Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program[2017BT01Y093] ; National Science and Technology Major Projects for Major New Drugs Innovation and Development[2018ZX09711003-003-005] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDC01040100] ; NSF[CHE-1111761] ; Taishan Scholars Program[tsqn201909170] ; Innovative Leader of Qingdao Program[19-3-2-26-zhc] ; Pilot National Laboratory for Marine Science and Technology[QNLM202001] ; Zhejiang University ; Sun Yat-Sen University
WOS关键词	MOLECULAR-DYNAMICS ; DISCOVERY ; CORONAVIRUSES ; PREDICTIONS ; CHLOROQUINE ; ACCURATE
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	NATL ACAD SCIENCES
WOS记录号	WOS:000587503000048
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/292577]
专题	中国科学院上海药物研究所
通讯作者	Cui, Jun; Zhan, Chang-Guo; Wang, Xin; Luo, Hai-Bin
作者单位	1.Hainan Univ, Sch Life & Pharmaceut Sci, Minist Educ, Key Lab Trop Biol Resources, Haikou 570228, Hainan, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Sun Yat Sen Univ, Sch Pharmaceut Sci, Guangdong Prov Key Lab New Drug Design & Evaluat, Guangzhou 510006, Peoples R China 4.Ocean Univ China, Ctr Innovat Marine Drug Screening & Evaluat, Sch Med & Pharm, Qingdao 266100, Peoples R China 5.Lanzhou Univ, Sch Life Sci, Lanzhou 734000, Peoples R China 6.Sun Yat Sen Univ, Sch Life Sci, Key Lab Gene Funct & Regulat, State Key Lab Biocontrol,Minist Educ MOE, Guangzhou 510006, Peoples R China 7.High Performance Comp Ctr, Pilot Natl Lab Marine Sci & Technol, Qingdao 266237, Peoples R China 8.Marine Biomed Res Inst Qingdao, Qingdao 266100, Peoples R China 9.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 10.Guangzhou Med Univ, Guangzhou Women & Childrens Med Ctr, Guangzhou Inst Pediat, State Key Lab Resp Dis, Guangzhou 510623, Peoples R China
推荐引用方式 GB/T 7714	Li, Zhe,Li, Xin,Huang, Yi-You,et al. Identify potent SARS-CoV-2 main protease inhibitors via accelerated free energy perturbation-based virtual screening of existing drugs[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2020,117(44):27381-27387.
APA	Li, Zhe.,Li, Xin.,Huang, Yi-You.,Wu, Yaoxing.,Liu, Runduo.,...&Luo, Hai-Bin.(2020).Identify potent SARS-CoV-2 main protease inhibitors via accelerated free energy perturbation-based virtual screening of existing drugs.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,117(44),27381-27387.
MLA	Li, Zhe,et al."Identify potent SARS-CoV-2 main protease inhibitors via accelerated free energy perturbation-based virtual screening of existing drugs".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 117.44(2020):27381-27387.