e-Pharmacophore model-guided design of potential DprE1 inhibitors: synthesis, in vitro antitubercular assay and molecular modelling studies

Abstract Tuberculosis continues to wreak havoc worldwide and caused around 1.4 million deaths in 2019. Hence, our pursuit of developing novel antitubercular compounds, we are reporting the e-Pharmacophore-based design DprE1 (decaprenylphosphoryl-ribose 2′-oxidase) inhibitors. In present work, have developed a four-feature e-Pharmacophore model based on receptor–ligand cavity protein (PDB ID 4P8C) mapped previous reported library compounds against it. The were ranked phase screen score, insights obtained from their alignment used some compounds. designed docked with extra-precision mode using Glide module Maestro, Schrodinger. Some derivatives like B1, B2, B4, B5 B12 showed comparable docking score (docking > − 6.0) respect co-crystallized ligand. synthesized characterized. vitro activity was carried out Mycobacterium tuberculosis H37Rv (ATCC27294) strain agar dilution method, minimum inhibitory concentration (MIC) determined. compound MIC value 1.56 μg/ml which better than standard drug ethambutol (3.125 μg/ml). Compounds B7 B11 found be equipotent ethambutol. Cytotoxicity studies Vero cell lines proved that these non-cytotoxic. Molecular dynamic simulation study also suggests will form stable complex show crucial H-bond interaction LYS418 residue. Further enzyme inhibition required validate findings.