Repurposing FDA-approved drugs for COVID-19: targeting the main protease through multi-phase in silico approach

The COVID-19 pandemic has created an urgent need for effective therapeutic agents. The SARS-CoV-2 Main Protease (M^pro) plays a crucial role in viral replication and immune evasion, making it a key target for drug development. While several studies have explored M^pro inhibition, identifying FDA-approved drugs with potential efficacy remains a critical research focus.

This study aims to identify FDA-approved drugs that could inhibit SARS-CoV-2 M^pro. Using computational screening, we seek compounds that share structural similarities with a known co-crystallized ligand (PRD_002214) and exhibit strong binding affinity to the enzyme, providing viable candidates for COVID-19 treatment.

A systematic in silico approach was used, screening 3009 FDA-approved drugs. The initial screening focused on structural similarity to PRD_002214 (PDB ID: 6LU7), followed by molecular docking studies to predict binding affinity. Promising compounds were further analyzed through molecular dynamics (MD) simulations to evaluate their stability and interactions with M^pro over 100 ns.

Of the 3009 FDA-approved drugs screened, 74 were selected for initial evaluation. After refinement, 28 compounds underwent docking analysis, with eight showing strong binding potential to M^pro.

Molecular docking assessed the binding affinity and interaction of the selected compounds with M^pro. MD simulations were conducted on the top compound, Atazanavir, to study its dynamic interactions. MM-GBSA, PLIP, and PCAT analyses were used to validate binding affinity and interactions.

Eight compounds, including Carfilzomib, Atazanavir, Darunavir, and others, exhibited promising binding affinities. Among them, Atazanavir showed the highest binding strength and was selected for further MD simulation studies. These simulations revealed that Atazanavir forms stable interactions with M^pro, demonstrating favorable binding and dynamic stability. The binding affinity was further confirmed through MM-GBSA, PLIP, and PCAT analyses, supporting Atazanavir's potential as an effective M^pro inhibitor.

In silico results suggest that Atazanavir is a promising candidate for targeting SARS-CoV-2 M^pro, with strong binding affinity and dynamic stability. These findings support its potential as a lead compound for further preclinical and clinical testing, though in vitro and in vivo validation are needed to confirm its therapeutic efficacy against COVID-19.