Identification of promising molecules against MurD ligase from Acinetobacter baumannii: insights from comparative protein modelling, virtual screening, molecular dynamics simulations and MM/PBSA analysis.

Acinetobacter baumannii, an opportunistic bacterium of the multidrug-resistant (MDR) ESKAPE family of pathogens, is responsible for 2-10% infections associated with all gram-negative bacteria. The hospital-acquired nosocomial infections caused by A.baumannii include deadly diseases like ventilator-associated pneumonia, bacteremia, septicemia and urinary tract infections (UTI). Over the last 3 years, it has evolved into multiple strains demonstrating high antibiotic resistance against a wide array of antibiotics. Hence, it becomes imperative to identify novel drug-like molecules to treat such infections effectively. UDP-N-acetylmuramoyl-L-alanine-D-glutamate ligase (MurD) is an essential enzyme of the Mur family which is responsible for peptidoglycan biosynthesis, making it a unique and ideal drug target. Initially, a homology modelling approach was employed to predict the three-dimensional model of MurD from A. baumannii using MurD from Escherichia coli (PDB ID: 4UAG) as a suitable structural template. Subsequently, an optimised model of MurD was subjected to virtual high-throughput screening (vHTS) against a ZINC library of ~ 642,759 commercially available molecules to identify promising lead compounds demonstrating high binding affinities towards it. From the screening process, four promising molecules were identified based on the estimated binding affinities (ΔG), estimated inhibition constants (Ki), catalytic residue interactions and drug-like properties, which were then subjected to molecular dynamics (MD) simulation studies to reflect the physiological state of protein molecules in vivo equivalently. The binding free energies of the selected MurD-ligand complexes were also calculated using MM/PBSA (molecular mechanics with Poisson-Boltzmann and surface area solvation) approach. Finally, the global dynamics along with binding free energy analysis suggested that ZINC19221101 (ΔG = - 62.6 ± 5.6 kcal/mol) and ZINC12454357 (ΔG = - 46.1 ± 2.6 kcal/mol) could act as most promising candidates for inhibiting the function of MurD ligase and aid in drug discovery and development against A.baumannii. Graphical abstract.