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
Cytochromes P450 (CYPs) catalyse diverse reactions and are key enzymes in fungal primary and secondary metabolism, and xenobiotic detoxification. CYP enzymatic properties and substrate specificity determine the reaction outcome. However, CYP-mediated reactions may also be influenced by their redox partners. Filamentous fungi with numerous CYPs often possess multiple microsomal redox partners, cytochrome P450 reductases (CPRs). Our objective was to functionally characterize two endogenous fungal cytochrome P450 systems and elucidate the putative physiological roles of CPR1 and CPR2 in the plant pathogenic ascomycete Cochliobolus lunatus. When reconstituted with CPR1, CYP53A15 converts benzoic acid and 3-methoxybenzoic acid differently, as when the redox partner is CPR2. Our studies also indicate that CPR1 is important in primary metabolism, whereas CPR2 plays a role elsewhere.
COBISS.SI-ID: 4729882