Identification of promising methionine aminopeptidase enzyme inhibitors: A combine study of comprehensive virtual screening and dynamics simulation study.

Methionine aminopeptidase (MetAP) enzymes play a critical role in bacterial cell survival by cleaving formyl-methionine initiators at N-terminal of nascent protein, a process which is vital in proper protein folding. This makes MetAP an attractive and novel antibacterial target to unveil promising antibiotics. In this study, the crystal structure of MetAP was used in structure-based virtual screening of drug libraries such as Asinex antibacterial library and Comprehensive Marine Natural Products Database (CMNPD) to identify promising lead molecules against the enzyme. This shortlisted three drug molecules; BDE-25098678, BDE-30686468 and BDD_25351157 as most potent leads that showed strong binding to the MetAP enzyme. The static docked conformation of the compounds to the MetAP was reevaluated in molecular dynamics simulation studies. The analysis observed the docked complexes as stable structure with no major local or global deviations noticed. These findings suggest the formation of strong intermolecular docked complexes, which showed stable dynamics and atomic level interactions network. The binding free energy analysis predicted net MMGBSA energy of complexes as: BDE-25098678 (-73.41 kcal/mol), BDE-30686468 (-59.93 kcal/mol), and BDD_25351157 (-75.39 kcal/mol). In case of MMPBSA, the complexes net binding energy was as; BDE-25098678 (-77.47 kcal/mol), BDE-30686468 (-69.47 kcal/mol), and BDD_25351157 (-75.6 kcal/mol). Further, the compounds were predicted to follow the famous Lipinski rule of five and have non-toxic, non-carcinogenic and non-mutagenic profile. The screened compounds might be used in experimental test to highlight the real anti- MetAP activity.