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

• Due to resistance to azoles there is desperate need of non-azole antifungal agents.
• A predictive pharmacophore model of CYP 51 inhibitors has been developed.
• The validated pharmacophore has been used to mine the chemical compound database.
• Docking and antimicrobial assay confirmed the potency of NSC 1215 and 1520 compound.
• The permeation study of NSC 1215 and 1520 revealed their high absorption capability.

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.

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