In recent years several promising antifungal targets have been under exploration. One of such is also fungal CYP53, family of highly conserved proteins observed in a number of pathogenic fungi, such as Aspergillus fumigatus and Gibberella zeae. In our recent study we identified benzoate para-hydroxylase (CYP53A15 or BPH) as a unique enzyme involved in detoxification of benzoate, a key intermediate in metabolism of aromatic compounds in fungi. High specificity and absence of homologue in higher eukaryotes assign CYP53A15 as interesting drug target. We have also revealed inhibition of CYP53A15 with natural compounds, such as isoeugenol, thymol, trans-cinnamic acid and shown their antifungal potential. Among 25 cinnamic acid derivatives tested, 4 compounds have shown antifungal potential. Two of them were also evaluated as inhibitors of CYP53A15 activity and were selected for further optimization of new lead structures.
COBISS.SI-ID: 5192218
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
In the work presented here, we have built reliable structural CYP53A15 homology model to perform virtual screening and molecular docking of library of compounds in active site. Compounds were selected from diverse commercial sources, based on molecular weight, number of ring systems, hetero atoms, H-bond donors or acceptors interactions with the heme iron. 40 compounds were obtained and evaluated in vitro in functional assays such as CO-differential spectrum, substrate binding spectrum and RP- HPLC analysis. Compounds were also tested In vivo with fungal growth inhibition assay. We selected compounds I26 and I30, based on potent antifungal activity and good inhibition of CYP53A15 enzyme activity, for new lead structures in antifungal drug research.
COBISS.SI-ID: 5192474