Towards the first inhibitors of trihydroxynaphthalene reductase from Curvularia lunata: synthesis of artificial substrate, homology modelling and initial screening

Mojca Brunskole; Bogdan Stefane; Karmen Zorko; Marko Anderluh; Jure Stojan; Tea Lanisnik Rizner; Stanislav Gobec

doi:10.1016/j.bmc.2008.04.066

Towards the first inhibitors of trihydroxynaphthalene reductase from Curvularia lunata: synthesis of artificial substrate, homology modelling and initial screening

Bioorg Med Chem. 2008 Jun 1;16(11):5881-9. doi: 10.1016/j.bmc.2008.04.066. Epub 2008 Apr 29.

Authors

Mojca Brunskole¹, Bogdan Stefane, Karmen Zorko, Marko Anderluh, Jure Stojan, Tea Lanisnik Rizner, Stanislav Gobec

Affiliation

¹ Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia.

PMID: 18482840
DOI: 10.1016/j.bmc.2008.04.066

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Ascomycota
Benzopyrans / chemical synthesis*
Benzopyrans / metabolism
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology
Fungal Proteins / antagonists & inhibitors*
Fungal Proteins / chemistry*
Fungal Proteins / metabolism
Melanins / antagonists & inhibitors
Melanins / biosynthesis
Models, Molecular*
Molecular Sequence Data
Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors*
Oxidoreductases Acting on CH-CH Group Donors / chemistry*
Oxidoreductases Acting on CH-CH Group Donors / metabolism
Recombinant Proteins / antagonists & inhibitors
Recombinant Proteins / chemistry
Recombinant Proteins / metabolism
Structural Homology, Protein*
Substrate Specificity

Substances

2,3-dihydro-2,5-dihydroxy-4H-benzopyran-4-one
Benzopyrans
Enzyme Inhibitors
Fungal Proteins
Melanins
Recombinant Proteins
tetrahydroxynaphthalene reductase
Oxidoreductases Acting on CH-CH Group Donors