3D-QSAR Studies Combined with Virtual Screening to Identify Novel Inhibitors of N-Acetyl Glucosamine 1-Phosphate Uridyltransferase from Mycobacterium Tuberculosis

The emergence of drug resistant tuberculosis poses a serious concern globally and researchers are in rigorous search for new drugs to fight against the disease. Recently, the bacterial GlmU protein (N-acetylglucosamine-1-phosphate uridyltransferase), involved in peptidoglycan, lipopolysaccharide and techoic acid synthesis, has been identified to be crucial for cell wall synthesis and survival of bacteria. The absence of this enzyme in humans makes it an important and attractive target to develop drugs for the treatment of this lethal disease. In the present study, pharmacophore mapping studies followed by 3D-QSAR analyses were undertaken for a set of 27 molecules reported to be inhibitors of GlmU. A three point pharmacophore with two hydrogen bond acceptors (A) and one hydrogen bond donor (D) as pharmacophoric features were developed. The generated model showed reasonable predictive power, with a correlation coefficient Q2=0.5701. The external validation indicated that our 3D-QSAR model possessed high predictive powers with R02 value of 0.9607 and rm2and rp2 values of 0.5100 and 0.5893 respectively. This model was then employed as 3D search query to virtually screen against public compound libraries (May bridge chemical libraries) in order to identify new scaffolds. We have identified six diverse non-peptidic scaffolds which were based on the pharmacophore fitness, docking score, interacting amino acids and ADME properties for drug-likeness that can be experimentally validated.