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

Haiping Zhang; Yang Yang; Junxin Li; Min Wang; Konda Mani Saravanan; Jinli Wei; Justin Tze-Yang Ng; Md Tofazzal Hossain; Maoxuan Liu; Huiling Zhang; Xiaohu Ren; Yi Pan; Yin Peng; Yi Shi; Xiaochun Wan; Yingxia Liu; Yanjie Wei

doi:10.1371/journal.pcbi.1008489

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

PLoS Comput Biol. 2020 Dec 31;16(12):e1008489. doi: 10.1371/journal.pcbi.1008489. eCollection 2020 Dec.

Authors

Haiping Zhang¹, Yang Yang², Junxin Li³, Min Wang⁴, Konda Mani Saravanan¹, Jinli Wei², Justin Tze-Yang Ng⁵, Md Tofazzal Hossain^{1

6}, Maoxuan Liu³, Huiling Zhang¹, Xiaohu Ren⁷, Yi Pan⁸, Yin Peng⁹, Yi Shi⁴, Xiaochun Wan³, Yingxia Liu², Yanjie Wei¹

Affiliations

¹ Center for High Performance Computing, Joint Engineering Research Center for Health Big Data Intelligent Analysis Technology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China.
² Shenzhen Key Laboratory of Pathogen and Immunity, National Clinical Research Center for infectious disease, State Key Discipline of Infectious Disease, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen, China.
³ Shenzhen Laboratory of Human Antibody Engineering, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, University City of Shenzhen, Shenzhen, China.
⁴ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
⁵ School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
⁶ University of Chinese Academy of Sciences, Shijingshan District, Beijing, China.
⁷ Institute of Toxicology, Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
⁸ Department of Computer Science, Georgia State University, Atlanta, Georgia, United States of America.
⁹ Department of Pathology, School of Medicine, Shenzhen University, Shenzhen, China.

Abstract

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 0.008μM and 9.453 μM, 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aminopterin / analogs & derivatives*
Aminopterin / chemistry
Aminopterin / pharmacology
Animals
Antiviral Agents / pharmacology*
Azithromycin / chemistry
Azithromycin / pharmacology
COVID-19 Drug Treatment
Chlorocebus aethiops
Computer Simulation
Deep Learning
Drug Evaluation, Preclinical / methods*
Drug Repositioning*
Molecular Dynamics Simulation
RNA-Dependent RNA Polymerase / antagonists & inhibitors*
RNA-Dependent RNA Polymerase / chemistry
SARS-CoV-2 / physiology*
Vero Cells
Virus Replication / drug effects

Substances

10-propargyl-10-deazaaminopterin
Antiviral Agents
Azithromycin
RNA-Dependent RNA Polymerase
Aminopterin

Grants and funding

This work was partly supported by the National Key Research and Development Program of China under Grant No. 2018YFB0204403 (Y.W.) and 2019YFA0906100 (X.W.); Strategic Priority CAS Project XDB38000000 to Y.W., National Science and Technology Major Project under Grant No. 2018ZX10101004 (Y.Y.), National Science Foundation of China under Grant no. U1813203 (Y.W.); the National Natural Youth Science Foundation of China (Grant no. 31601028: Y.P.); the Shenzhen Basic Research Fund under Grant no. JCYJ20190807170801656 (J.L.), JCYJ20180507182818013 (Y.W.), JCYJ20170413093358429 (Y.W.), and the SIAT Innovation Program for Excellent Young Researchers (J.L.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.