The SARS‐CoV‐2 main protease (M pro ) remains a critical therapeutic target for COVID‐19 intervention. In this study, we employed a comprehensive in silico repurposing strategy to identify FDA‐approved drugs with potential inhibitory activity against M pro . An initial molecular fingerprint screening of 3009 FDA‐approved compounds, based on similarity to the cocrystallized inhibitor X77, yielded 150 similar candidates. Subsequent structural similarity filtering reduced the list to 30 compounds, which were subjected to molecular docking. Apixaban demonstrated strong binding affinity and favorable interaction patterns within the M pro active site and was selected for further investigation. A 100‐ns molecular dynamics simulation comparing the apo and holo forms confirmed the structural stability of the M pro –apixaban complex. Apixaban remained stably positioned within the binding pocket, while reduced RMSF values in key active‐site residues indicated apixaban‐induced stabilization. Molecular mechanics–generalized Born surface area (MM‐GBSA) analysis estimated a binding free energy of −22.19 kcal/mol, with van der Waals interactions contributing predominantly to complex stability. Per‐residue decomposition highlighted significant contributions from Met165 and Gln189. Protein–ligand interaction fingerprinting (ProLIF) and protein–ligand interaction profiler (PLIP) analyses revealed persistent hydrogen bonds and hydrophobic contacts involving Asn142, Cys145, Gln189, Thr190, Gln192, and Arg188. Principal component analysis of trajectories (PCAT) demonstrated apixaban‐induced modulation of collective motions and partial closure of the binding pocket. Importantly, this study provides detailed atomistic insights into the potential interaction of apixaban with M pro . Together, these findings offer a plausible molecular rationale for its inhibitory activity and support further experimental and pharmacological evaluation of apixaban as a potential therapeutic candidate targeting SARS‐CoV‐2 M pro .
Metwaly et al. (Thu,) studied this question.