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

Zhe Li, Xin Li, Yi-You Huang, Yaoxing Wu, Runduo Liua, Lingli Zhou, Yuxi Lin, Deyan Wu, Lei Zhang, Hao Liu, Ximing Xu, Kunqian Yu, Yuxia Zhang, Jun Cui, Chang-Guo Zhan, Xin Wang, Hai-Bin Luo

10.1073/pnas.2010470117

Research curated

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.

Source: PubMed

Related molecules

Name	Synonyms	Genes
Candesartan cilexetil
Candesartan
Oxytetracycline
Valganciclovir
Roxatidine acetate
Omeprazole
Sulfacetamide
Cimetidine
Maribavir
Disulfiram
Chloroquine
3C-like protease	3CLpro, Mpro, SARS coronavirus main peptidase, 3CLpro-SARS-CoV-2	rep, ORF1a-1b
Dipyridamole
Montelukast sodium
Atazanavir
Hydroxychloroquine	HCQ, Oxichlorochine, Oxichloroquine
Indinavir

Related interactions

Target	Drug	Type	Result
3C-like protease	Dipyridamole	Computational	positive
3C-like protease	Candesartan cilexetil	Computational	positive
3C-like protease	Montelukast sodium	Computational	positive
3C-like protease	Candesartan	Computational	positive
3C-like protease	Oxytetracycline	Computational	positive
3C-like protease	Valganciclovir	Computational	positive
3C-like protease	Roxatidine acetate	Computational	positive
3C-like protease	Omeprazole	Computational	positive
3C-like protease	Sulfacetamide	Computational	positive
3C-like protease	Cimetidine	Computational	positive
3C-like protease	Chloroquine	Computational	positive
3C-like protease	Hydroxychloroquine	Computational	positive
3C-like protease	Indinavir	Computational	positive
3C-like protease	Maribavir	Computational	positive
3C-like protease	Disulfiram	Computational	positive
3C-like protease	Atazanavir	Computational	positive