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. 2025 Apr 7;49(3):233-246.
doi: 10.55730/1300-0152.2741. eCollection 2025.

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

Murat Serilmez  1   2 , Anwar Abuelrub  2 , Ismail Erol  2   3 , Serdar Durdaği  2   4
Affiliations

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

Murat Serilmez et al. Turk J Biol. .

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.

Keywords: COVID-19; covalent docking; molecular dynamics simulation; molecular mechanics-generalized Born surface area.

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Figures

Figure 1
Figure 1
(A) The orientation of top-scored small molecules in the binding pocket of RdRp during a nucleophilic addition to a double bond reaction, involving (B) bremelanotide, (C) histrelin, (D) lanreotide, and (E) leuprolide.
Figure 2
Figure 2
(A) The orientation of top-scored small molecules in the binding pocket of the TMPRSS2 protein during a nucleophilic addition reaction, involving (B) isavuconazonium, (C) ivosidenib, and (D) tenapanor.
Figure 3
Figure 3
(A) The orientation of top-scored small molecules in the binding pocket of the Mpro protein during a betalactam reaction, involving (B) azlocillin, (C) cefiderocol, and (D) sultamicillin.
Figure 4
Figure 4
(A) The orientation of top-scored small molecules in the binding pocket of the ACE2 protein during betalactam reaction, involving (B) cefiderocol, (C) cefoperazone, and (D) ceftolozane.
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