title: Towards the first inhibitors of trihydroxynaphthalene reductase from Curvularia lunata: synthesis of artificial substrate, homology modelling and initial screening.
abstract: Trihydroxynaphthalene reductase (3HNR) is an essential enzyme in the biosynthesis of fungal melanin and it represents an emerging target for the development of new fungicides and antimicotics. To promote the discovery of new inhibitors, an improved chemical synthesis of the artificial substrate 2,3-dihydro-2,5-dihydroxy-4H-benzopyran-4-one (DDBO) was developed. A series of compounds were screened on 3HNR from Curvularia lunata, a known plant pathogen and an opportunistic human pathogen, and several structurally diverse hits were obtained. Homology modelling of 3HNR from C. lunata can explain their binding modes and will enable further structure-based design of new and improved inhibitors.
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia.
authors.forename: Mojca
authors.initials: M
authors.lastname: Brunskole
authors.forename: Bogdan
authors.initials: B
authors.lastname: Stefane
authors.forename: Karmen
authors.initials: K
authors.lastname: Zorko
authors.forename: Marko
authors.initials: M
authors.lastname: Anderluh
authors.forename: Jure
authors.initials: J
authors.lastname: Stojan
authors.forename: Tea
authors.initials: T
authors.lastname: Lanisnik Rizner
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
mesh_terms: D000595:Amino Acid Sequence; D001203:Ascomycota; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D005656:Fungal Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D008543:Melanins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008958:Models, Molecular; D008969:Molecular Sequence Data; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D040681:Structural Homology, Protein; D013379:Substrate Specificity
chemical_list: C111394:2,3-dihydro-2,5-dihydroxy-4H-benzopyran-4-one; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D005656:Fungal Proteins; D008543:Melanins; D011994:Recombinant Proteins; C086024:tetrahydroxynaphthalene reductase; D044925:Oxidoreductases Acting on CH-CH Group Donors