FDA-approved drugs as potential covalent inhibitors of key SARS-CoV-2 proteins: an in silico approach

Abstract

Background/aim: The COVID-19 pandemic caused by SARS-CoV-2 necessitated rapid development of effective therapeutics, prompting this study to identify potential inhibitors targeting key viral and host proteins: RNA-dependent RNA polymerase (RdRp), main protease (Mpro), transmembrane serine protease 2 (TMPRSS2), and angiotensin-converting enzyme 2 (ACE2). Methods: We used covalent docking and molecular dynamics (MD) simulations to screen FDA-approved compounds against these targets using diverse covalent reaction mechanisms. Top-ranking compounds underwent further evaluation through MD simulations to assess binding stability and conformational dynamics. Results: Several promising drug repurposing candidates were identified: bremelanotide, lanreotide, histrelin, and leuprolide as potential RdRp inhibitors, azlocillin, cefiderocol, and sultamicillin for Mpro inhibition, tenapanor, isavuconazonium, and ivosidenib targeting TMPRSS2, and cefiderocol, cefoperazone, and ceftolozane as potential ACE2 inhibitors. Conclusion: This study provides valuable insights into repurposing existing drugs as potential COVID-19 therapeutics by targeting crucial viral proteins. However, further experimental validation and preclinical studies are necessary to confirm the efficacy and safety of these compounds before consideration for clinical application. © 2025 Elsevier B.V., All rights reserved.