A novel virtual screening procedure identifies Pralatrexate as inhibitor of SARS-CoV-2 RdRp and it reduces viral replication in vitro

Zhang, Haiping1; Yang, Yang2; Li, Junxin3; Wang, Min4; Saravanan, Konda Mani1; Wei, Jinli2; Ng, Justin Tze-Yang5; Hossain, Md Tofazzal1,6; Liu, Maoxuan3; Zhang, Huiling1; Ren, Xiaohu7; Pan, Yi8; Peng, Yin9; Shi, Yi4; Wan, Xiaochun3; Liu, Yingxia2; Wei, Yanjie1

2020-12-01

10.1371/journal.pcbi.1008489

PLoS Computational Biology   影响因子和分区

1553-734X

1553-7358

["The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus poses serious threats to the global public health and leads to worldwide crisis. No effective drug or vaccine is readily available. The viral RNA-dependent RNA polymerase (RdRp) is a promising therapeutic target. A hybrid drug screening procedure was proposed and applied to identify potential drug candidates targeting RdRp from 1906 approved drugs. Among the four selected market available drug candidates, Pralatrexate and Azithromycin were confirmed to effectively inhibit SARS-CoV-2 replication in vitro with EC50 values of 0.008 mu M and 9.453 mu M, respectively. For the first time, our study discovered that Pralatrexate is able to potently inhibit SARS-CoV-2 replication with a stronger inhibitory activity than Remdesivir within the same experimental conditions. The paper demonstrates the feasibility of fast and accurate anti-viral drug screening for inhibitors of SARS-CoV-2 and provides potential therapeutic agents against COVID-19.","Author summary","Currently, a novel coronavirus called SARS-COV-2 is spreading across many parts of the world. Unfortunately, there is still a lack of effective drugs against the virus. Additionally, it usually takes much longer time to develop a new drug using traditional methods. Thus, it is now better to rely on some alternative methods to develop drugs that can treat such a disease effectively. In this paper, we have proposed a deep learning and molecular dynamics simulation based hybrid drug screening procedure for identifying potential drug candidates targeting RdRp from 1906 market available drugs. Our screening have successfully identified a FDA-approved drug called Pralatrexate that strongly inhibits the replication of 2019-nCoV in vitro with EC50 values of 0.008 mu M. This work demonstrated the feasibility of accurate virtual drug screening for inhibitors of SARS-CoV-2 and provides potential therapeutic agents against COVID-19."]

SCI ; EI

英语

通讯

National Key Research and Development Program of China["2018YFB0204403","2019YFA0906100"] ; National Science and Technology Major Project[2018ZX10101004] ; National Science Foundation of China[U1813203] ; National Natural Youth Science Foundation of China[31601028] ; Shenzhen Basic Research Fund["JCYJ20190807170801656","JCYJ20180507182818013","JCYJ20170413093358429"] ; Strategic Priority CAS Project[XDB38000000]

Biochemistry & Molecular Biology ; Mathematical & Computational Biology

Biochemical Research Methods ; Mathematical & Computational Biology

WOS:000605330800002

PUBLIC LIBRARY SCIENCE

Web of Science

1.Chinese Acad Sci, Ctr High Performance Comp, Joint Engn Res Ctr Hlth Big Data Intelligent Anal, Shenzhen Inst Adv Technol, Shenzhen, Guangdong, Peoples R China
2.Southern Univ Sci & Technol, Hosp Affiliated 1, Shenzhen Peoples Hosp 3,Shenzhen Key Lab Pathogen, State Key Discipline Infect Dis,Natl Clin Res Ctr, Shenzhen, Peoples R China
3.Chinese Acad Sci, Univ City Shenzhen, Inst Biomed & Biotechnol, Shenzhen Inst Adv Technol,Shenzhen Lab Human Anti, Shenzhen, Peoples R China
4.Chinese Acad Sci, Inst Microbiol, CAS Key Lab Pathogen Microbiol & Immunol, Beijing, Peoples R China
5.Nanyang Technol Univ, Sch Biol Sci, Singapore, Singapore
6.Univ Chinese Acad Sci, Beijing, Peoples R China
7.Shenzhen Ctr Dis Control & Prevent, Inst Toxicol, Shenzhen, Peoples R China
8.Georgia State Univ, Dept Comp Sci, Atlanta, GA 30303 USA
9.Shenzhen Univ, Sch Med, Dept Pathol, Shenzhen, Peoples R China

Zhang, Haiping,Yang, Yang,Li, Junxin,et al. A novel virtual screening procedure identifies Pralatrexate as inhibitor of SARS-CoV-2 RdRp and it reduces viral replication in vitro[J]. PLoS Computational Biology,2020,16(12).

Zhang, Haiping.,Yang, Yang.,Li, Junxin.,Wang, Min.,Saravanan, Konda Mani.,...&Wei, Yanjie.(2020).A novel virtual screening procedure identifies Pralatrexate as inhibitor of SARS-CoV-2 RdRp and it reduces viral replication in vitro.PLoS Computational Biology,16(12).

Zhang, Haiping,et al."A novel virtual screening procedure identifies Pralatrexate as inhibitor of SARS-CoV-2 RdRp and it reduces viral replication in vitro".PLoS Computational Biology 16.12(2020).