title: 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.
authors.affiliation: Department of Pharmacy, Banasthali University, P.O. Banasthali, Rajasthan 304022, India.
authors.forename: Aarti
authors.initials: A
authors.lastname: Singh
authors.affiliation: Department of Pharmacy, Banasthali University, P.O. Banasthali, Rajasthan 304022, India. Electronic address: paliwalsarvesh@yahoo.com.
authors.forename: Sarvesh Kumar
authors.initials: SK
authors.lastname: Paliwal
authors.affiliation: Department of Pharmacy, Banasthali University, P.O. Banasthali, Rajasthan 304022, India.
authors.forename: Mukta
authors.initials: M
authors.lastname: Sharma
authors.affiliation: Department of Pharmacy, Banasthali University, P.O. Banasthali, Rajasthan 304022, India.
authors.forename: Anupama
authors.initials: A
authors.lastname: Mittal
authors.affiliation: Department of Pharmacy, Banasthali University, P.O. Banasthali, Rajasthan 304022, India.
authors.forename: Swapnil
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Pharmacy, Banasthali University, P.O. Banasthali, Rajasthan 304022, India.
authors.forename: Jai Prakash
authors.initials: JP
authors.lastname: Sharma
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry* / Q000494:pharmacology; D001234:Aspergillus niger / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D002175:Candida / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D002176:Candida albicans / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D041022:Candida tropicalis / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D020134:Catalytic Domain; D062126:Databases, Chemical; D025141:Drug Resistance, Fungal; D005656:Fungal Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D057166:High-Throughput Screening Assays; D057927:Hydrophobic and Hydrophilic Interactions; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D010539:Permeability; D017433:Protein Structure, Secondary; D051381:Rats; D017208:Rats, Wistar; D058886:Sterol 14-Demethylase / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014584:User-Computer Interface
chemical_list: D058888:14-alpha Demethylase Inhibitors; D000935:Antifungal Agents; D005656:Fungal Proteins; D058886:Sterol 14-Demethylase
keywords: Ligand based pharmacophore modeling; Molecular docking; Non-azoles; Virtual screening