3D QSAR Pharmacophore Based Virtual Screening, ADME Analysis and Estimation of MM/GBSA binding Free Energies of Azoles as a Potential Inhibitor of DprE1 for Mycobacterium Tuberculosis

Abstract Decaprenylphosphoryl - D – ribose – 2 –epimerase (DprE1) is a promising drug target to identify new anti- TB drugs against drug resistant tuberculosis. DprE1 helps in cell wall biosynthesis through Decaprenyl-phosphoryl d-arabinose pathway. Inhibition of DprE1 results in blocking of cell wall biosynthesis, causing death of mycobacterium tuberculosis. In current studies, a set of thirty triazole molecules having antitubercular activity were selected for pharmacophore 3D QSAR studies. The generated common pharmacophore hypothesis (AHRRR.172) consists of one acceptor (A), one hydrophobic (H), and three aromatic rings (R). The resulted pharmacophore model recorded with good statistical results, R2 = 0.71, Q2 = 0.54 and other parameters F = 45, RMSE = 0.41. This model further investigated to identify pharmacophoric features which are crucial for biological activity. The resultant pharmacophore model was used to screen ZINC chemical database molecules to identify potent lead molecules against DprE1 enzyme. The resultant hit molecules were recorded with dihydroquinonolin 2-one and Pyrazolo [1, 5] pyramidin 5-one scaffold and this information could be helpful to design new potent anti-tuberculosis agent. Further, these molecules along with co-crystal ligand were utilized for the estimation of physicochemical properties and followed by binding mode analysis.