Towards the first inhibitors of trihydroxynaphthalene reductase from Curvularia lunata: synthesis of artificial substrate, homology modelling and initial screening.
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.
Brunskole
Mojca
M
Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia.
Stefane
Bogdan
B
Zorko
Karmen
K
Anderluh
Marko
M
Stojan
Jure
J
Lanisnik Rizner
Tea
T
Gobec
Stanislav
S
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
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