In silico high-throughput virtual screening and molecular dynamics simulation study to identify inhibitor for AdeABC...

Emergence of multi-drug resistant strains of Acinetobacter baumannii has caused significant health problems and is responsible for high morbidity and mortality. Overexpression of AdeABC efflux system is one of the major mechanisms. In this study, we have focused on overcoming the drug resistance by identifying inhibitors that can effectively bind and inhibit integral membrane protein, AdeB of this efflux pump. We performed homology modeling to generate structure of AdeB using MODELLER v9.16 followed by model refinement using 3D-Refine tool and validated using PSVS, ProsaWeb, ERRAT, etc. The energy minimization of modeled protein was done using Protein preparation wizard application included in Schrodinger suite. High-throughput virtual screening of 159,868 medicinal compounds against AdeB was performed using three sequential docking modes (i.e. HTVS, SP and XP). Furthermore, absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis was done using QIKPROP. The selected 123 compounds were further analyzed for binding free energy by molecular mechanics (using prime MM-GBSA). We have also performed enrichment study (ROC curve analysis) to validate our docking results. The selected molecule and its interaction with AdeB were validated by molecular dynamics simulation (MDS) using GROMACS v5.1.4. In silico high-throughput virtual screening and MDS validation identified ZINC01155930 ((4R)-3-(cycloheptoxycarbonyl)-4-(4-etochromen-3-yl)-2-methyl-4,6,7,8-tetrahydroquinolin-5-olate) as a possible inhibitor for AdeB. Hence, it might be a suitable efflux pump inhibitor worthy of further investigation in order to be used for controlling infections caused by Acinetobacter baumannii.