title: Shape and pharmacophore-based virtual screening to identify potential cytochrome P450 sterol 14α-demethylase inhibitors.
abstract: Sterol 14α-demethylase (CYP51) is a cytochrome P450 heme thiolate containing enzyme involved in biosynthesis of membrane sterols, including sterol in animals, ergosterol in fungi, and a variety of C24-modified sterols in plants and protozoa. Several clinical drugs have been developed to reduce the impact of fungal diseases, but their clinical uses have been limited by the emergence of drug resistance and insufficiencies in their antifungal activity. Therefore, in order to identify potential CYP51 inhibitors, we have implemented a virtual screening (VS) protocol by using both phase shape and pharmacophore model (AHHRR) against Asinex, ChemBridge and Maybridge databases. A filtering protocol, including Lipinski filter, number of rotatable bonds and different precisions of molecular docking was applied in hits selection. The results indicated that both shape-based and pharmacophore-based screening yielded the best result with potential inhibitors. The searched compounds were also evaluated with ADME properties, which show excellent pharmacokinetic properties under the acceptable range. We identified potential CYP51 inhibitors for further investigation, they could also be employed to design ligands with enhanced inhibitory potencies and to predict the potencies of analogs to guide synthesis/or prepare synthetic antifungal analogs against CYP51.
authors: Computer-Aided Drug Design and Molecular Modeling Lab, Department of Bioinformatics, Alagappa University, Karaikudi, Tamil Nadu, India.
authors: Karnati Konda
authors: KK
authors: Reddy
authors: Sanjeev Kumar
authors: SK
authors: Singh
authors: Sunil Kumar
authors: SK
authors: Tripathi
authors: Chandrabose
authors: C
authors: Selvaraj
authors: Venkatesan
authors: V
authors: Suryanarayanan
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D000935:Antifungal Agents / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D001393:Azoles / Q000737:chemistry / Q000627:therapeutic use; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D062126:Databases, Chemical; D006801:Humans; D058886:Sterol 14-Demethylase / Q000737:chemistry / Q000378:metabolism*
chemical_list: D058888:14-alpha Demethylase Inhibitors; D000935:Antifungal Agents; D001393:Azoles; D003577:Cytochrome P-450 Enzyme System; D058886:Sterol 14-Demethylase