title: Novel inhibitors of trihydroxynaphthalene reductase with antifungal activity identified by ligand-based and structure-based virtual screening.
abstract: Curvularia lunata is a dark pigmented fungus that is the causative agent of several diseases in plants and in both immunodeficient and immunocompetent patients. 1,8-Dihydroxynaphthalene-melanin is found in the cell wall of C. lunata and is believed to be the important virulence factor of dematiaceous fungi. Trihydroxynaphthalene reductase is an enzyme of the 1,8-dihydroxynaphthalene-melanin biosynthetic pathway, and it thus represents an emerging target for the development of novel fungicides and antimycotics. In the present study, we describe novel inhibitors of trihydroxynaphthalene reductase from C. lunata. These inhibitors were identified by ligand-based three-dimensional similarity searching and docking to a homology-built model and by subsequent biochemical and antifungal evaluation. Discovery of competitive inhibitors with K(i) values in low micromolar and even nanomolar concentration range proves the aplicability of homology-built model of 3HNR for hit finding by virtual screening methods.
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 Svegelj
authors.forename: Samo
authors.initials: S
authors.lastname: Turk
authors.forename: Boris
authors.initials: B
authors.lastname: Brus
authors.forename: Tea
authors.initials: T
authors.lastname: Lanisnik Rizner
authors.forename: Jure
authors.initials: J
authors.lastname: Stojan
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry* / Q000494:pharmacology; D001667:Binding, Competitive; D003198:Computer Simulation; D005656:Fungal Proteins / Q000037:antagonists & inhibitors*; D057166:High-Throughput Screening Assays; D008024:Ligands; D015394:Molecular Structure; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins; D008024:Ligands; D054852:Small Molecule Libraries; C086024:tetrahydroxynaphthalene reductase; D044925:Oxidoreductases Acting on CH-CH Group Donors