In-silico approach to identify novel potent inhibitors against GraR of S. aureus

With rising antibiotic resistance at alarming rates in S. aureus, a major human pathogen, it is important to identify targets for new antimicrobial therapies. A number of two-component systems (TCS) have been implicated in S. aureus resistance to several antibiotics. The glycopeptide-resistance associated TCS, GraSR, is involved in cationic antimicrobial peptides (CAMPs) resistance through the regulation of mprF, dltABCD, and vraFG operons. GraS is a sensor histidine kinase, while GraR is a response regulator transcription factor, which is potential drug target. In lieu of the significance of GraSR in antibiotic resistance and the lack of structural studies on GraR, we undertook to determine the GraR structure through homology modelling. A series of small molecules were virtually screened and the top-scored molecules were analyzed for different pharmacophore properties and assessed for their binding potency to GraR (IC50). Further, a molecular dynamics simulation study of GraR-ligand complexes revealed that the predicted molecules exhibited good binding affinities at the dimerization interface of GraR. Thus, these molecules could be suitable inhibitors for the GraR-mediated signalling processes, which may be further utilized to develop novel antimicrobial agents against S. aureus.