In silico evaluation of imidazopyridine compounds targeting ACE2: molecular dynamics and binding energy analysis

Angiotensin-converting enzyme 2 (ACE2) regulates cardiovascular function and serves as the SARS-CoV-2 entry receptor, making it a dual therapeutic target. Most drug development focuses on the virus rather than exploring broader host-directed protective strategies. We hypothesize that imidazopyridine derivatives may serve as candidate ACE2 binders for experimental evaluation with potential applications in both antiviral and cardiovascular contexts. Here, we present an integrated computational study of 67 imidazopyridine derivatives as ACE2 modulators. Molecular docking, MM-GBSA binding free energy calculations, and 100-ns molecular dynamics simulations identified compound 28 as a lead candidate with the highest binding affinity among all tested derivatives (Glide score: -9.97 kcal/mol; MM-GBSA: -79.26 kcal/mol). This compound formed stable interactions with catalytic residues and preserved structural integrity throughout simulations. Principal component analysis revealed three conformational states, indicating that compound 28 maintains stable binding while preserving the conformational flexibility necessary for catalytic function. These results identify imidazopyridines as candidate binders for experimental validation and establish a computational framework to guide future experimental studies of host-directed ACE2 modulators.