Computational investigations of gram-negative bacteria phosphopantetheine adenylyltransferase inhibitors using 3D-QSAR, molecular docking and molecular dynamic simulations.

Phosphopantetheine adenylyltransferase (PPAT) has been recognized as a promising target to develop novel antimicrobial agents, which is a hexameric enzyme that catalyzes the penultimate step in coenzyme A biosynthesis. In this work, molecular modeling study was performed with a series of PPAT inhibitors using molecular docking, three-dimensional qualitative structure-activity relationship (3D-QSAR) and molecular dynamic (MD) simulations to reveal the structural determinants for their bioactivities. Molecular docking study was applied to understand the binding mode of PPAT with its inhibitors. Subsequently, 3D-QSAR model was constructed to find the features required for different substituents on the scaffolds. For the best comparative molecular field analysis (CoMFA) model, the Q2 and R2 values of which were calculated as 0.702 and 0.989, while they were calculated as 0.767 and 0.983 for the best comparative molecular similarity index analysis model. The statistical data verified the significance and accuracy of our 3D-QSAR models. Furthermore, MD simulations were carried out to evaluate the stability of the receptor-ligand contacts in physiological conditions, and the results were consistent with molecular docking studies and 3D-QSAR contour map analysis. Binding free energy was calculated with molecular mechanics generalized born surface area approach, the result of which coincided well with bioactivities and demonstrated that van der Waals accounted for the largest portion. Overall, our study provided a valuable insight for further research work on the recognition of potent PPAT inhibitors.Communicated by Ramaswamy H. Sarma.