Potential COVID-19 papain-like protease PLpro inhibitors: repurposing FDA-approved drugs

Valentina L Kouznetsova; Aidan Zhang; Mahidhar Tatineni; Mark A Miller; Igor F Tsigelny

doi:10.7717/peerj.9965

Potential COVID-19 papain-like protease PL^pro inhibitors: repurposing FDA-approved drugs

PeerJ. 2020 Sep 18:8:e9965. doi: 10.7717/peerj.9965. eCollection 2020.

Authors

Valentina L Kouznetsova¹, Aidan Zhang², Mahidhar Tatineni¹, Mark A Miller¹, Igor F Tsigelny^{1

3

4}

Affiliations

¹ San Diego Supercomputer Center, University of California, San Diego, La Jolla, CA, USA.
² REHS Program at San Diego Dupercomputer Center, University of California, San Diego, La Jolla, CA, USA.
³ Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
⁴ Science, CureMatch Inc., San Diego, CA, USA.

Abstract

Using the crystal structure of SARS-CoV-2 papain-like protease (PL^pro) as a template, we developed a pharmacophore model of functional centers of the PL^pro inhibitor-binding pocket. With this model, we conducted data mining of the conformational database of FDA-approved drugs. This search identified 147 compounds that can be potential inhibitors of SARS-CoV-2 PL^pro. The conformations of these compounds underwent 3D fingerprint similarity clusterization, followed by docking of possible conformers to the binding pocket of PL^pro. Docking of random compounds to the binding pocket of protease was also done for comparison. Free energies of the docking interaction for the selected compounds were lower than for random compounds. The drug list obtained includes inhibitors of HIV, hepatitis C, and cytomegalovirus (CMV), as well as a set of drugs that have demonstrated some activity in MERS, SARS-CoV, and SARS-CoV-2 therapy. We recommend testing of the selected compounds for treatment of COVID-19.

Keywords: COVID-19; Computational drug design; Drugs repurposing; Papain-like protease.

Grants and funding

R01 GM126463/GM/NIGMS NIH HHS/United States