title: Virtual screening yields inhibitors of novel antifungal drug target, benzoate 4-monooxygenase.
abstract: 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 employed two parallel virtual screening protocols and evaluated highest scoring hit compounds by analyzing the spectral binding interactions, by surveying the antifungal activity, and assessing the inhibition of catalytic activity. On the basis of combined results, we selected 3-methyl-4-(1H-pyrrol-1-yl)benzoic acid (compound 2) as the best candidate for hit-to-lead follow-up in the antifungal drug discovery process.
authors.affiliation: Faculty of Medicine, Institute of Biochemistry, University of Ljubljana, Vrazov trg 2, SI-1000 Ljubljana, Slovenia. sabina.berne@mf.uni-lj.si
authors.forename: Sabina
authors.initials: S
authors.lastname: Berne
authors.forename: Barbara
authors.initials: B
authors.lastname: Podobnik
authors.forename: Neja
authors.initials: N
authors.lastname: Zupanec
authors.forename: Metka
authors.initials: M
authors.lastname: Novak
authors.forename: Nada
authors.initials: N
authors.lastname: Kraševec
authors.forename: Samo
authors.initials: S
authors.lastname: Turk
authors.forename: Branka
authors.initials: B
authors.lastname: Korošec
authors.forename: Ljerka
authors.initials: L
authors.lastname: Lah
authors.forename: Erika
authors.initials: E
authors.lastname: Šuligoj
authors.forename: Jure
authors.initials: J
authors.lastname: Stojan
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
authors.forename: Radovan
authors.initials: R
authors.lastname: Komel
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry*; D001203:Ascomycota / Q000737:chemistry*; D050565:Benzoate 4-Monooxygenase / Q000037:antagonists & inhibitors*; D001565:Benzoates / Q000737:chemistry*; D020134:Catalytic Domain; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D015195:Drug Design; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry*; D005656:Fungal Proteins / Q000037:antagonists & inhibitors*; D007527:Isoenzymes / Q000737:chemistry; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011758:Pyrroles / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry; D012248:Rhodotorula / Q000737:chemistry*; D040681:Structural Homology, Protein
chemical_list: C580805:3-methyl-4-(1H-pyrrol-1-yl)benzoic acid; D000935:Antifungal Agents; D001565:Benzoates; D004791:Enzyme Inhibitors; D005656:Fungal Proteins; D007527:Isoenzymes; D011758:Pyrroles; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System; D050565:Benzoate 4-Monooxygenase