Pharmacophore identification of ascofuranone, potent inhibitor of cyanide-insensitive alternative oxidase of Trypanosoma brucei
Pharmacophore identification of ascofuranone, potent inhibitor of cyanide-insensitive alternative oxidase of Trypanosoma brucei
复制标题
DOI：
10.1093/jb/mvs135
复制
发表时间：
2013-03-01
影响因子：
2.7
通讯作者：
Kita, Kiyoshi
中科院分区：
文献类型：
--
作者：
Saimoto, Hiroyuki;Kido, Yasutoshi;Kita, Kiyoshi
布氏锥虫是引起人类非洲锥虫病（HAT）的寄生虫。该寄生虫依赖于氰化物不敏感的锥虫交替氧化酶（TAO）进行其重要的有氧呼吸。抗坏血酸呋喃酮（AF）是一种有效的、特异性的亚纳摩尔TAO醌醇氧化酶抑制剂，由于哺乳动物宿主缺乏HAT酶，因此是一种潜在的对HAT具有选择性的新型药物。为了阐明AF的抑制机理和酶与底物的相互作用，设计合成了AF衍生物，并对其构效关系进行了评价。在这里，我们确定了与TAO相互作用的AF药效团。详细的抑制概况表明，1-甲酰基和6-羟基，这可能有助于分子内氢键和/或作为氢键供体，负责与酶的直接相互作用。
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.