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

2025    Serilmez, Murat; Abuelrub, Anwar; Erol, İsmail; Durdagı, Serdar

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 proteins: RNA-dependent RNA polymerase (RdRp), main protease (Mpro), transmembrane serine protease 2 (TMPRSS2), and angiotensin-converting enzyme 2 (ACE2).

Methods: We employed covalent docking and molecular dynamics simulations to screen FDA-approved compounds against these targets using diverse covalent reaction mechanisms. Top-ranking compounds underwent further evaluation through molecular dynamics simulations to assess binding stability and conformational dynamics.

Results: Several promising drug repurposing candidates were identified: Bremelanotide, Lanreotide, histerlin, and Leuprolide as potential RdRp protein inhibitors; Azlocilin, 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 clinical studies are necessary to confirm the efficacy and safety of these compounds before consideration for clinical application.