Pharmacophore modeling and structure-based virtual screening to identify potent inhibitors targeting LuxP of Vibrio harveyi

The main aim of the study is to identify molecules that can disrupt quorum sensing (QS) system of Vibrio harveyi and therefore perhaps the production of toxins. Recently, a novel class of dioxazaborocane derivatives has been found to block AI-2 QS by targeting LuxPQ, but the mechanism of protein inhibition is still unclear. In order to investigate the possible binding modes, all the derivatives were docked into the binding site of LuxP using induced fit docking (IFD). The computed binding affinity is in good agreement with the experimental data. Resultant protein-ligand complexes were simulated using Desmond module and the result revealed better binding of ligands in the binding site of LuxP. Both pharmacophore- and structure-based virtual screening was performed to identify novel hits against LuxP. A filtering protocol, including lipinski filters, number of rotatable bonds and three levels of docking precisions were used for the selection of hits with specific properties. The virtual screening results were then combined and analyzed, which retrieved six hits with significant Glide score, binding affinity toward LuxP. The pharmacokinetic properties of the retrieved hits are in the acceptable range. Enrichment calculation was performed to validate the final hits, to discriminate the active compounds from the inactive compounds. The identified hits could serve as a base for further drug development against LuxP of Vibrio harveyi.