Molecular modelling, docking and dynamics studies of biotin carboxyl carrier protein of acetyl-CoA carboxylase to discover potential inhibitors

Background: Designing drug molecules targeting biotin carboxyl carrier protein of acetyl-CoA carboxylase (AccB), a novel common drug target among the pathogens of infective endocarditis (IE), would be imperative for IE therapy. Methods: Homology modelling of AccB was performed in complex with biotin using Modeller9v8. DOPE score,PROCHECK, ProSA and ProQ analyses were used for model validation. Allosteric site residues of AccB were determined using PyMOL. The structural analogs of biotin were searched from the Ligand.Info metadatabase tool to compile an in-house library. Structure-based virtual screening for AccB was performed using Maestro v9.2. Molecular dynamic (MD) simulations for AccB - lead1 docking complex were performed using Desmond v3.0. Results: The AccB structure was evaluated as reliable one for docking analysis. The prepared in-house library comprised of 357 biotin analogs. The structure-based virtual screening on AccB and in-house library led to identification of two lead molecules with better binding affinity compared to biotin (XP Gscore -2.216 kcal/mol). Lead1 showed the lowest XP Gscore of -5.847 kcal/mol with strong hydrogen bond network and good van der Waal interactions with AccB. Stable nature of the docking interactions was reproduced through MD simulations after 10 ns. Interpretation: The binding orientations of lead1 were well in agreement with binding orientations of existing inhibitors. MD simulations shed light on natural dynamics of the docking complex in solution on different timescales. Conclusions: Lead1 could, therefore, be considered for designing potent inhibitor of infective endocarditis.