An integrated protocol of virtual screening involving molecular docking, pharmacophore probing, and simulations was established to identify small novel molecules targeting crucial residues involved in the penicillin binding proteins (PBPs) involved in bacterial cell wall biosynthesis. An excellent approach was made utilizing ligand and structure-based pharmacophore to identify common features and structure-based docking with respect to PBPs in leading to the development of novel inhibitors possessing new scaffolds. To our delight, multiple-substituted triazine derivatives series bearing a novel scaffold, of which structure is remarkably different from the existing β-lactam inhibitors, were designed. A structure-based pharmacophore mapping was developed to explore the binding sites of PBPs which were taken into consideration. Subsequently, virtual screening, ADMET searches were at work to narrow down the proposed hits to be forwarded as a potential drug likes candidates. Further, the binding patterns of the best-proposed hits were explored to understand the deeper insight for its structural optimization by employing it on molecular dynamic simulations of 500ps. Selectivity profile for the most promising candidates was studied, revealing significantly C series molecules C15 was found to be the most potent compounds among designed library. The proposed hits can be forwarded for further study against PBPs involved in bacterial peptidoglycan cell wall biosynthesis.



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