Acinetobacter baumannii is an opportunistic pathogen with ability to cause serious infection such as bacteremia, ventilator associated pneumonia, and wound infections. As strains of A. baumannii are resistant to almost all clinically used antibiotics and with the emergence of carbapenems resistant phenotypes warrants the search for novel antibiotics. Considering this, herein, a series of computer aided drug designing approach was utilized to search novel chemical scaffolds that bind stronger to MurE ligase enzyme of A. baumannii, which is involved peptidoglycan synthesis. The work identified LAS_22461675, LAS_34000090 and LAS_51177972 compounds as promising binding molecules with MurE enzyme having binding energy score of -10.5 kcal/mol, -9.3 kcal/mol and -8.6 kcal/mol, respectively. The compounds were found to achieve docked inside the MurE substrate binding pocket and established close distance chemical interactions. The interaction energies were dominated by van der Waals and less contributions were seen from hydrogen bonding energy. The dynamic simulation assay predicted the complexes stable with no major global and local changes noticed. The docked stability was also validated by MM/PBSA and MM/GBSA binding free energy methods. The net MM/GBSA binding free energy of LAS_22461675 complex, LAS_34000090 complex and LAS_51177972 complex is -26.25 kcal/mol, -27.23 kcal/mol and -29.64 kcal/mol, respectively. Similarly in case of MM-PBSA, the net energy value was in following order; LAS_22461675 complex (-27.67 kcal/mol), LAS_34000090 complex (-29.94 kcal/mol) and LAS_51177972 complex (-27.32 kcal/mol). The AMBER entropy and WaterSwap methods also confirmed stable complexes formation. Further, molecular features of the compounds were determined that predicted compounds to have good druglike properties and pharmacokinetic favorable. The study concluded the compounds to good candidates to be tested by in vivo and in vitro experimental assays.Communicated by Ramaswamy H. Sarma.
Keywords: Acinetobacter baumannii; Asinex antibacterial library; MurE ligase; molecular dynamic simulation.