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Identify potent SARS-CoV-2 main protease inhibitors via accelerated free energy perturbation-based virtual screening of existing drugs.
Li, Zhe; Li, Xin; Huang, Yi-You; Wu, Yaoxing; Liu, Runduo; Zhou, Lingli; Lin, Yuxi; Wu, Deyan; Zhang, Lei; Liu, Hao; Xu, Ximing; Yu, Kunqian; Zhang, Yuxia; Cui, Jun; Zhan, Chang-Guo; Wang, Xin; Luo, Hai-Bin.
  • Li Z; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, 510006 Guangzhou, People's Republic of China.
  • Li X; Center for Innovative Marine Drug Screening & Evaluation, School of Medicine and Pharmacy, Ocean University of China, 266100 Qingdao, China.
  • Huang YY; School of Life Sciences, Lanzhou University, 734000 Lanzhou, China.
  • Wu Y; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, 510006 Guangzhou, People's Republic of China.
  • Liu R; Ministry of Education (MOE) Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, 510006 Guangzhou, China.
  • Zhou L; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, 510006 Guangzhou, People's Republic of China.
  • Lin Y; Ministry of Education (MOE) Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, 510006 Guangzhou, China.
  • Wu D; Center for Innovative Marine Drug Screening & Evaluation, School of Medicine and Pharmacy, Ocean University of China, 266100 Qingdao, China.
  • Zhang L; School of Life Sciences, Lanzhou University, 734000 Lanzhou, China.
  • Liu H; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, 510006 Guangzhou, People's Republic of China.
  • Xu X; Ministry of Education (MOE) Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, 510006 Guangzhou, China.
  • Yu K; High Performance Computing Center, Pilot National Laboratory for Marine Science and Technology, 266237 Qingdao, China.
  • Zhang Y; Center for Innovative Marine Drug Screening & Evaluation, School of Medicine and Pharmacy, Ocean University of China, 266100 Qingdao, China.
  • Cui J; Marine Biomedical Research Institute of Qingdao, 266100 Qingdao, China.
  • Zhan CG; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, China.
  • Wang X; University of Chinese Academy of Sciences, 100049 Beijing, China.
  • Luo HB; Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, 510623 Guangzhou, China.
Proc Natl Acad Sci U S A ; 117(44): 27381-27387, 2020 11 03.
Article in English | MEDLINE | ID: covidwho-867659
ABSTRACT
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 (Mpro). 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 Mpro The most potent one is dipyridamole (inhibitory constant Ki = 0.04 µM) which has shown promising therapeutic effects in subsequently conducted clinical studies for treatment of patients with COVID-19. Additionally, hydroxychloroquine (Ki = 0.36 µM) and chloroquine (Ki = 0.56 µM) were also found to potently inhibit SARS-CoV-2 Mpro We anticipate that the FEP-ABFE prediction-based virtual screening approach will be useful in many other drug repurposing or discovery efforts.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Protease Inhibitors / Viral Nonstructural Proteins / Drug Repositioning / Betacoronavirus Type of study: Prognostic study Limits: Humans Language: English Journal: Proc Natl Acad Sci U S A Year: 2020 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Protease Inhibitors / Viral Nonstructural Proteins / Drug Repositioning / Betacoronavirus Type of study: Prognostic study Limits: Humans Language: English Journal: Proc Natl Acad Sci U S A Year: 2020 Document Type: Article