Targeting Outer Membrane Protein Component AdeC for the Discovery of Efflux Pump Inhibitor against AdeABC Efflux Pump of Multidrug Resistant Acinetobacter baumannii

摘要

The structure and functioning of multidrug efflux systems provide us with a better understanding of the transport of various antibiotics, thus giving a path for the discovery of effective compounds for combating the multidrug resistance in Acinetobacter baumannii . In the present study, a number of computational techniques have been used to search for an inhibitor for the RND efflux pump, AdeABC, of A. baumannii targeting specifically its outermost component, i.e., AdeC. We have prepared the three-dimensional structure for AdeC using MODELLER v9.16 and identified its active binding site using SiteMap. Using high-throughput virtual screening, we identified compounds from a large library of biogenic compounds on the basis of their effective interaction at the binding site of AdeC. The validation of docking step was performed by plotting ROC curve (enrichment calculations). The docked complexes were further analyzed for their binding free energies by molecular mechanics using Generalized Born model and Solvent Accessibility (MMGBSA). The molecular dynamics simulation was performed for AdeC-ZINC77257599 complex using GROMACS. The present rational drug designing, molecular mechanics and molecular dynamics data provided an inhibitor, i.e, ZINC77257599 [(3R,4Z,6E,8E)-3-hydroxy-2,2,4-trimethyl-10-oxazol-5-yl-deca-4,6,8-trienamide], for the outer membrane protein component (AdeC) of efflux pump AdeABC of A. baumannii .