Identifying novel inhibitors against drug-resistant mutant CYP-51 Candida albicans: A computational study to combat fungal infections

Candida albicans (C. albicans) is an opportunistic pathogen that poses a significant risk to immunocompromised individuals while also existing as a normal inhabitant of the oral cavity, throat, gastrointestinal tract, and genitourinary system in healthy populations. Our study aimed to identify novel inhibitors capable of binding to the mutant cytochrome P450 family 51 (CYP-51) protein, targeting resistant C. albicans infections.

To achieve this, we utilized a pharmacophore ligand-based model for virtual screening of compound libraries. Molecular docking was performed using Maestro (Schrodinger), and ADMET analysis was conducted to assess drug-likeness properties, including absorption, distribution, metabolism, excretion, and toxicity. Additionally, density functional theory (DFT) calculations, molecular dynamics (MD) simulations, and free binding energy (MMPBSA) calculations were carried out to refine our findings.

From an initial pool of 11,022 hits sourced from PubChem libraries, six compounds were selected based on their superior interactions with the mutant CYP-51 protein, identified through pharmacophore mapping using the Pharma IT tool. Each of these six compounds was docked into the active site of the mutant CYP-51 protein, with CP-3 demonstrating the highest binding affinity (-10.70 kcal/mol). CP-3 also exhibited favorable ADMET characteristics, suggesting strong potential as a drug candidate.

Further, MD simulations confirmed the stability of CP-3 within the active site of the mutant CYP-51 protein, reinforcing its potential as an effective antagonist. Our computational study highlights CP-3 as a promising inhibitor of mutant CYP-51, offering a potential pathway for antifungal drug development. However, additional in vitro and in vivo studies are required to validate its pharmacokinetic properties and therapeutic efficacy as a novel antifungal agent. ML390