In silico and in vitro screening to identify structurally diverse non-azole CYP51 inhibitors as potent antifungal agent

Abstract

The problem of resistance to azole class of antifungals is a serious cause of concern to the medical fraternity and thus there is an urgent need to identify non-azole scaffolds with high affinity for lanosterol 14α-demethylase (CYP51). In view of this we have attempted to identify novel non-azole CYP51 inhibitors through the application of pharmacophore based virtual screening and in vitro evaluation. A rigorously validated pharmacophore model comprising of 2 hydrogen bond acceptor and 2 hydrophobic features has been developed and used to mine NCI database. Out of 265 retrieved hits, NSC 1215 and 1520 have been chosen on the basis of Lipinski's rule of five, fit and estimated values. Both the hits were docked into the active site of CYP51. In view of high fit value and CDocker score, NSC 1215 and 1520 have been subjected to in vitro microbiological assay. The result reveals that NSC 1215 and 1520 are active against Candida albicans, Candida parapsilosis, Candida tropicalis, and Aspergillus niger. In addition to this the absorption characteristics of both the hits have also been determined using the rat sac technique and permeation in order of NSC 1520>NSC 1215 has been observed.

Keywords: Ligand based pharmacophore modeling; Molecular docking; Non-azoles; Virtual screening.