Novel potential inhibitor discovery against tyrosyl-tRNA synthetase from Staphylococcus aureus by virtual screening, molecular dynamics, MMPBSA and QMMM simulations

The abuse and overuse of antibiotics is the main responsible for the raising antibiotic resistance among bacteria and as a consequence the of diseases severity and treatment complications. Staphylococcus aureus (S. aureus) can cause severe bloodstream infection, endocarditis and skin infection with an annual incidence of twenty-six cases per one hundred thousand people and approximately 30% of them are lethal. Among the different and diverse resistance mechanisms, S. aureus enzyme tyrosyl-tRNA synthetase (YRS) was selected as emerging target to be employed to the state of the art computer-aided drug design. At this regard, a library including the 15,387 chemicals from the Zinc database was screened by means of AutoDock Vina software. The selected hit (ZINC59675144), upon its docking binding energy and comparison with the positive control (SB284485), was subjected to molecular dynamics (MD) simulation. Following the MD, the physico-chemical parameters of the free or inhibitor-bound YRS complexes were analyzed and discussed. Our molecular modelling investigation, along with QM/MM studies, suggests that ZINC59675144 has impressive properties as a potential inhibitor of YRS, and also can be utilised as lead compound for further improvements. In addition, the ADME analysis displayed that whole physicochemical characteristics are compatible for human administration.