Molecular insights on analogs of imidazo[1,2-a]pyridine, azaindole, and pyridylurea towards ParE using pharmacophore modeling, molecular docking, and dynamic simulation

Abstract

Topoisomerase IV E (ParE) of Streptococcus pneumonia, a subunit of topoisomerase IV, ensures the regulation of DNA topology and demonstrated to be a bactericidal drug target. Availability of crystal structure of S. pneumonia ParE in complex with one of the thiazolo[5,4-b]pyridinones facilitated us to employ combined computational approach to explore the putative binding mode of selected inhibitors into the catalytic pocket of ParE. We developed a five-point pharmacophore model using 67 molecules having pIC50 ranging from 4.795 to 8.522. The generated model was validated using enrichment calculations. The three-dimensional quantitative structure–activity relationship (3D-QSAR) model showed a high correlation coefficient (R 2 = 0.892), cross-validation coefficient (Q 2 = 0.744), and F value (119) at three component partial least squares (PLS) factor. Using the crystallographic bound compound, the effectiveness of the flexible docking protocol was validated as evident from the low root mean square deviation (0.96 A). A 10-ns molecular dynamic simulation confirmed the stability of the 4MOT-ligand complex. Further, superposition of conformation of compound 45 after MD simulation and compound 45’s poses of XP-docking and 3D-QSAR model showed similar orientation. The molecular information obtained from docking and 3D-QSAR analysis was employed to propose new inhibitors. These findings provide insight for the design of molecules with better ParE inhibitory activity.