经合理设计的锥虫硫醇还原酶选择性抑制剂。以吩噻嗪类及相关三环化合物作为先导结构。
Rationally designed selective inhibitors of trypanothione reductase. Phenothiazines and related tricyclics as lead structures.
作者信息
Benson T J, McKie J H, Garforth J, Borges A, Fairlamb A H, Douglas K T
机构信息
Department of Pharmacy, University of Manchester, U.K.
出版信息
Biochem J. 1992 Aug 15;286 ( Pt 1)(Pt 1):9-11. doi: 10.1042/bj2860009.
Abstract
Trypanothione reductase, an essential component of the anti-oxidant defences of parasitic trypanosomes and Leishmania, differs markedly from the equivalent host enzyme, glutathione reductase, in the binding site for the disulphide substrate. Molecular modelling of this region suggested that certain tricyclic compounds might bind selectively to trypanothione reductase without inhibiting host glutathione reductase. This was confirmed by testing 30 phenothiazine and tricyclic antidepressants, of which clomipramine was found to be the most potent, with a K(i) of 6 microM, competitive with respect to trypanothione. Many of these compounds have been noted previously to have anti-trypanosomal and anti-leishmanial activity and thus they can serve as lead structures for rational drug design.
摘要
锥虫硫醇还原酶是寄生锥虫和利什曼原虫抗氧化防御系统的重要组成部分，在二硫键底物结合位点上与宿主的谷胱甘肽还原酶有显著差异。该区域的分子模型表明，某些三环化合物可能选择性地结合锥虫硫醇还原酶而不抑制宿主谷胱甘肽还原酶。对30种吩噻嗪和三环类抗抑郁药进行测试后证实了这一点，其中氯米帕明被发现活性最强，其抑制常数（K(i)）为6微摩尔，对锥虫硫醇具有竞争性。此前已注意到这些化合物中有许多具有抗锥虫和抗利什曼原虫活性，因此它们可作为合理药物设计的先导结构。
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