Fungal CYP53 enzymes are highly conserved proteins, involved in phenolic detoxification and have no homologues in higher eukaryotes, rendering them favorable drug targets. Aiming to discover novel CYP53 inhibitors, we employedtwo parallel virtual screening protocols and evaluated highest scoringhit compounds by analyzing the spectral binding interactions, by surveying the antifungal activity, and assessing the inhibition of catalytic activity. Based on combined results, we selected 3-methyl-4-(1H-pyrrol-1-yl)benzoic acid (compound 2) as the best candidate forhit-to-lead follow-up in the antifungal drug discovery process.
COBISS.SI-ID: 30257369
Aims:CYP53A15, from the sorghum pathogen Cochliobolus lunatus is involved in detoxification of benzoate, a key intermediate in aromatic compound metabolism in fungi. Because this enzyme is unique to fungi, it is a promising drug target in fungal pathogens of other eukaryotes.Methods and results:In our work we showed high antifungal activity of seven cinnamic acid derivatives against C. lunatus, and two other fungi, Aspergillus niger and Pleurotus ostreatus. In order to elucidate the mechanism of action of cinnamic acid derivatives with the most potent antifungal properties, we studied the interactions between these compounds and the active site of C. lunatus cytochrome P450, CYP53A15. Conclusion:We demonstrated that cinnamic acid and at least four of the 42 tested derivatives inhibit CYP53A15 enzymatic activity.Significance and impact of study:By identifying selected derivatives of cinnamic acid as possible antifungal drugs, and CYP53 family enzymes as their targets, we revealed a potential inhibitor-target system for antifungal drug development. This article is protected by copyright. All rights reserved.
COBISS.SI-ID: 31019737