Due to the concerning rise in the number of multiple- and prolonged-drug-resistant (MDR and XDR) Mycobacterium tuberculosis (Mtb) strains, unprecedented demand has been created to design and develop novel therapeutic drugs with higher efficacy and safety. In this study, with a focused view on implementing an in silico drug design pipeline, a diverse set of glycosylated flavonoids were screened against the Mtb cytochrome-P450 enzyme 121 (CYP121), which is established as an approved drug target for the treatment of Mtb infection. A total of 148 glycosylated flavonoids were screened using structure-based virtual screening against the crystallized ligand, i.e., the L44 inhibitor, binding pocket in the Mtb CYP121 protein. Following this, only the top six compounds with the highest binding scores (kcal/mol) were considered for further intermolecular interaction and dynamic stability using 100 ns classical molecular dynamics simulation. These results suggested a considerable number of hydrogen and hydrophobic interactions and thermodynamic stability in comparison to the reference complex, i.e., the CYP121-L44 inhibitor. Furthermore, binding free energy via the MMGBSA method conducted on the last 10 ns interval of MD simulation trajectories revealed the substantial affinity of glycosylated compounds with Mtb CYP121 protein against reference complex. Notably, both the docked poses and residual energy decomposition via the MMGBSA method demonstrated the essential role of active residues in the interactions with glycosylated compounds by comparison with the reference complex. Collectively, this study demonstrates the viability of these screened glycosylated flavonoids as potential inhibitors of Mtb CYP121 for further experimental validation to develop a therapy for the treatment of drug-resistant Mtb strains.
Keywords: CYP121; Mycobacterium tuberculosis; docking; molecular dynamic simulation; protein-ligand interaction.