Molecular docking, molecular dynamics simulation, and MM/PBSA analysis of ginger phytocompounds as a potential inhibitor of AcrB for treating multidrug-resistant Klebsiella pneumoniae infections

Abstract

The emergence of Multidrug resistance (MDR) in human pathogens has defected the existing antibiotics and compelled us to understand more about the basic science behind alternate anti-infective drug discovery. Soon, proteome analysis identified AcrB efflux pump protein as a promising drug target using plant-driven phytocompounds used in traditional medicine systems with lesser side effects. Thus, the present study aims to explore the novel, less toxic, and natural inhibitors of Klebsiella pneumoniae AcrB pump protein from 69 Zingiber officinale phyto-molecules available in the SpiceRx database through computational-biology approaches. AcrB protein’s homology-modelling was carried out to get a 3D structure. The multistep-docking (HTVS, SP, and XP) were employed to eliminate less-suitable compounds in each step based on the docking score. The chosen hit-compounds underwent induced-fit docking (IFD). Based on the XP GScore, the top three compounds, epicatechin (−10.78), 6-gingerol (−9.71), and quercetin (−9.09) kcal/mol, were selected for further calculation of binding free energy (MM/GBSA). Furthermore, the short-listed compounds were assessed for their drug-like properties based on in silico ADMET properties and Pa, Pi values. In addition, the molecular dynamics simulation (MDS) studies for 250 ns elucidated the binding mechanism of epicatechin, 6-gingerol, and quercetin to AcrB. From the dynamic binding free energy calculations using MM/PBSA, 6-gingerol exhibited a strong binding affinity towards AcrB. Further, the 6-gingerol complex’s energy fluctuation was observed from the free energy landscape. In conclusion, 6-gingerol has a promising inhibiting potential against the AcrB efflux pump and thus necessitates further validation through in vitro and in vivo experiments. Communicated by Ramaswamy H. Sarma