Computational Discovery of Novel CYP51 Inhibitors for Antifungal Therapy Against Aspergillus fumigatus

Lanosterol 14-alpha demethylase (CYP51), encoded by the Erg11 gene, is a crucial enzyme in pathogenic fungi. It catalyzes the demethylation of lanosterol to ergosterol, a vital component of fungal cell membranes. Inhibition of CYP51 disrupts ergosterol biosynthesis, compromises membrane integrity, and inhibits fungal growth, making it a key target for antifungal therapy. In this study, we employed a comprehensive computational approach comprising molecular docking, drug-likeness analysis, dynamics simulations, pharmacophoric feature modeling, ADMET profiling, and pharmacokinetic (PK) simulations to identify novel CYP51 inhibitors from a library of 1,200 plant-derived metabolites. Of these, 211 compounds exhibited stronger binding affinities than voriconazole, a widely used antifungal agent. The top 10 metabolites showed strong interactions with key substrate recognition sites (SRS1, SRS2, SRS4, and SRS6) of CYP51. MD simulations of the top three candidates, Boeravinone D, Nimbidin, and 7-acetyl neotrichilenone, revealed stable binding conformations primarily driven by non-polar interactions, as confirmed by MM/GBSA binding free energy calculations. Notably, Nimbidin exhibited the most favorable binding energetics, supported by Gibbs free energy and hydrogen bonding analyses. Principal component analysis (PCA) further indicated distinct and stable dynamic behaviors of the ligand-protein complexes. Pharmacokinetic simulations suggested that Boeravinone D and Nimbidin may maintain prolonged plasma concentrations, indicating strong therapeutic potential. All three candidates showed favorable ADMET profiles, although 7-acetyl neotrichilenone may require optimization to improve solubility. These findings identify Boeravinone D, Nimbidin, and 7-acetyl neotrichilenone as promising CYP51 inhibitors. Further in vitro and in vivo studies are warranted to validate their antifungal efficacy and advance them as potential therapeutic agents.