Structural basis of resistance to anti-cytochrome bc₁ complex inhibitors: implication for drug improvement.
Structural basis of resistance to anti-cytochrome bc₁ complex inhibitors: implication for drug improvement.
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DOI：
10.2174/138161282005140214163327
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发表时间：
2014
影响因子：
3.1
通讯作者：
Xia D
中科院分区：
文献类型：
--
作者：
Esser L;Yu CA;Xia D
耐药性的出现具有毁灭性的经济和社会后果，其中一个证明是呼吸成分细胞色素bc 1复合物抑制剂的兴衰，这是一个经过时间考验的高度有效的疾病控制目标。不幸的是，耐药机制是一个多变量问题，主要包括细胞色素B亚基基因突变，但也包括泛醇氧化和药代动力学效应的替代途径的激活。人们对设计具有新型结合模式和较低诱导耐药性发展倾向的新型bc 1抑制剂非常感兴趣。结合抑制剂前后bc 1配合物晶体学数据的积累为合理的药物设计提供了结构基础。特别是，细胞色素B亚基提供了两个不同的活性位点，可以靶向抑制-醌氧化位点和醌还原位点。本文综述了各种醌醇氧化和还原位点抑制剂抑制bc 1的结构信息、抑制剂结合模式、抑制剂结合活性位点侧链后的构象变化以及铁硫蛋白亚基的大规模结构域运动。结构数据分析提供了一个清晰的理解，在哪里和为什么现有的抑制剂失败，并指向有前途的替代品。
The emergence of drug resistance has devastating economic and social consequences, a testimonial of which is the rise and fall of inhibitors against the respiratory component cytochrome bc1 complex, a time tested and highly effective target for disease control. Unfortunately, the mechanism of resistance is a multivariate problem, including primarily mutations in the gene of the cytochrome b subunit but also activation of alternative pathways of ubiquinol oxidation and pharmacokinetic effects. There is a considerable interest in designing new bc1 inhibitors with novel modes of binding and lower propensity to induce the development of resistance. The accumulation of crystallographic data of bc1 complexes with and without inhibitors bound provides the structural basis for rational drug design. In particular, the cytochrome b subunit offers two distinct active sites that can be targeted for inhibition - the quinol oxidation site and the quinone reduction site. This review brings together available structural information of inhibited bc1 by various quinol oxidation- and reduction-site inhibitors, the inhibitor binding modes, conformational changes upon inhibitor binding of side chains in the active site and large scale domain movements of the iron-sulfur protein subunit. Structural data analysis provides a clear understanding of where and why existing inhibitors fail and points towards promising alternatives.