Identification of potential non-nucleoside MraY inhibitors for tuberculosis chemotherapy using structure-based virtual screening.

The efforts to limit the spread of the tuberculosis epidemic have been challenged by the rise of drug-resistant strains of (), the causative agent of tuberculosis. It is critical to discover new chemical scaffolds acting on novel or unexploited targets to beat this drug-resistant pathogen. MraY (phospho-MurNAc-pentapeptide translocase or translocase I) is an validated target for antibacterials-discovery. MraY is inhibited by nucleoside-based natural products that suffer from poor efficacy. The current study is focused on discovering novel chemical entities, particularly, non-nucleoside small molecules, as MraY inhibitors possessing antituberculosis activity. In the absence of any reported X-ray crystal structures of MraY, we used a homology model-based virtual screening approach combined with the ligand-based e-pharmacophore screening. We screened ∼12 million commercially available compounds from the ZINC15 database using GOLD software. The resulting hits were filtered using a 2-pronged screening method comprising e-pharmacophore hypotheses and docking against the MraY homology model using Glide. Further clustering based on Glide scores and optimal binding interactions resulted in 15 hits. We performed molecular dynamics (MD) simulations for the three best-ranking compounds and one other poorer-ranking compound, out of the 15 hits, to analyze the interaction modes in detail. The MD simulations indicated stable interactions between the compounds and key residues in the MraY active site that are crucial for maintaining the enzymatic activity. These hits could advance the antibacterial drug discovery campaign to find new MraY inhibitors for tuberculosis treatment.Communicated by Ramaswamy H. Sarma.