The nosocomial infection outbreak caused by Pseudomonas aeruginosa remains a public health concern. Multi-drug resistant (MDR) strains of P. aeruginosa are rapidly spreading leading to a huge mortality rate because of the unavailability of promising antimicrobials. MurG glycotransferase [UDP-N-acetylglucosamine-N-acetylmuramyl (pentapeptide) pyrophosphoryl-undecaprenol N-acetylglucosamine transferase] is located at the plasma membrane and plays a key role in murein (peptidoglycan) biosynthesis in bacteria. Since MurG is required for bacterial cell wall synthesis and is non-homologous to Homo sapiens; it can be a potential target for the antagonist to treat P. aeruginosa infection. The discovery of high-resolution crystal structure of P. aeruginosa MurG offers an opportunity for the computational identification of its prospective inhibitors. Therefore, in the present study, the crystal structure of MurG (PDB ID: 3S2U) from P. aeruginosa was selected, and computational docking analyses were performed to search for functional inhibitors of MurG. IMPPAT (Indian medicinal plants, phytochemicals and therapeutic) phytomolecule database was screened by computational methods with MurG catalytic site. Docking results identified Theobromine (-8.881 kcal/mol), demethoxycurcumin (-8.850 kcal/mol), 2-alpha-hydroxycostic acid (-8.791 kcal/mol), aurantiamide (-8.779 kcal/mol) and petasiphenol (-8.685 kcal/mol) as a potential inhibitor of the MurG activity. Further, theobromine and demethoxycurcumin were subjected to MDS (molecular dynamics simulation) and free energy (MM/GBSA) analysis to comprehend the physiological state and structural stability of MurG-phytomolecules complexes. The outcomes suggested that these two phytomolecules could act as most favorable natural hit compounds for impeding the enzymatic action of MurG in P. aeruginosa, and thus it needs further validation by both in vitro and in vivo analysis. HIGHLIGHTSThe top phytomolecules such as theobromine, demethoxycurcumin, 2-alpha-hydroxycostic acid, aurantiamide and petasiphenol displayed promising binding with MurG catalytic domain.MurG complexed with theobromine and demethoxycurcumin showed the best interaction and stable by MD simulation at 100 ns.The outcome of MurG binding phytomolecules has expanded the possibility of hit phytomolecules validation.Communicated by Ramaswamy H. Sarma.
Keywords: ADMET drug prediction; IMPPAT database; MurG protein; Pseudomonas aeruginosa; molecular docking; molecular dynamic simulation.