Studies on the antibacterial activities and molecular mechanism of GyrB inhibitors by 3D-QSAR, molecular docking and molecular dynamics simulation

Abstract

DNA gyrase B (GyrB) plays a critical role in DNA replication, repair, recombination, and transcription and has become an attractive target for a number of antibacterial agents. In the present work, to better comprehend the structure–activity relationship and mechanism of action of novel series of GyrB inhibitors, a theoretical study of three-dimensional-quantitative structure–activity relationship (3D-QSAR), molecular docking, molecular dynamics (MD) simulations, and binding free energy analysis were performed. The results showed that CoMFA (R 2 cv = 0.591, R 2 pred = 0.7698) and CoMSIA (R 2 cv = 0.629, R 2 pred = 0.6848) models possessed robust stability and predictability. The derived contour maps of steric, electrostatic, and hydrogen bond donor field further displayed the modified information of these inhibitors. Molecular docking was further conducted to provide the initial binding conformation for MD simulations. Subsequently, MD simulations were applied to explore the key amino acids and binding modes at the active site. The binding free energy decomposition analysis further indicates that the residues Ile54, Glu55, Arg83, Ala85, Val86 and Thr128 are essential for the high selectivity of inhibitors. Overall, these results would serve as a significant guideline for the discovery and design of novel GyrB inhibitors.