title: Pharmacophore identification of ascofuranone, potent inhibitor of cyanide-insensitive alternative oxidase of Trypanosoma brucei.
abstract: Trypanosoma brucei is a parasite that causes human African trypanosomiasis (HAT). The parasites depend on the cyanide-insensitive trypanosome alternative oxidase (TAO) for their vital aerobic respiration. Ascofuranone (AF), a potent and specific sub-nanomolar inhibitor of the TAO quinol oxidase, is a potential novel drug with selectivity for HAT, because mammalian hosts lack the enzyme. To elucidate not only the inhibition mechanism but also the inhibitor-enzyme interaction, AF derivatives were designed and synthesized, and the structure-activity relationship was evaluated. Here we identified the pharmacophore of AF that interacts with TAO. The detailed inhibitory profiles indicated that the 1-formyl and 6-hydroxyl groups, which might contribute to intramolecular hydrogen bonding and/or serve as hydrogen-bonding donors, were responsible for direct interaction with the enzyme.
authors.affiliation: Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, Tottori 680-8552, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Saimoto
authors.forename: Yasutoshi
authors.initials: Y
authors.lastname: Kido
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Haga
authors.forename: Kimitoshi
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kita
mesh_terms: D000475:Alkenes / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012717:Sesquiterpenes / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014346:Trypanosoma brucei brucei / Q000201:enzymology* / Q000235:genetics; D014353:Trypanosomiasis, African / Q000469:parasitology
chemical_list: D000475:Alkenes; D004791:Enzyme Inhibitors; D010636:Phenols; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D012717:Sesquiterpenes; D010088:Oxidoreductases; C020094:duroquinol oxidase; C432586:ubiquinol oxidase; C006640:ascofuranone; C415745:ascochlorin