Subnanomolar inhibitor of cytochrome bc1 complex designed by optimizing interaction with conformationally flexible residues.
Subnanomolar inhibitor of cytochrome bc1 complex designed by optimizing interaction with conformationally flexible residues.
复制标题
通过优化与构象灵活残基的相互作用而设计的细胞色素 bc1 复合物的亚纳摩尔抑制剂。
DOI：
10.1021/ja905756c
复制
发表时间：
2010-01-13
影响因子：
15
通讯作者：
Yang, Guang-Fu
中科院分区：
文献类型：
--
作者：
Zhao, Pei-Liang;Wang, Le;Zhu, Xiao-Lei;Huang, Xiaoqin;Zhan, Chang-Guo;Wu, Jia-Wei;Yang, Guang-Fu
细胞色素bc（1）复合物（Cytochrome bc（1）complex，EC 1.10.2.2，bc（1））是光合细菌细胞呼吸链和光合机构的重要组成部分，已被确定为新药和农用杀菌剂的有希望的靶标。游离bc（1）及其与不同抑制剂的复合物的X-射线衍射结构显示，在不同抑制剂结合时，结合口袋中Phe 274的苯基表现出明显的构象柔性，从而优化了各自的π-π相互作用，而其他疏水残基的侧链表现出构象稳定性。因此，在本研究中，我们提出了一种优化具有构象柔性残基的pi-pi相互作用的策略，以设计和发现新的具有更高效力的bc（1）抑制剂。设计并合成了8个新化合物，其中化合物5c的K（i）值为570 pM，被认为是最有前途的药物或杀菌剂候选物，其活性明显高于市售的bc（1）抑制剂，包括嘧菌酯（AZ）、醚菌酯（KM）和吡唑醚菌酯（PY）。据我们所知，这是第一个通过基于结构的设计发现的bc（1）抑制剂，其效力为亚纳摩尔K（i）值。对于合成和测定的所有化合物，计算的结合自由能与从实验K（i）值导出的结合自由能相当好地相关，相关系数r（2）= 0.89。进一步的抑制动力学研究表明，5c对底物细胞色素c是非竞争性抑制剂，但对底物泛醇是竞争性抑制剂。由于它的亚纳摩尔K（i）效力和缓慢的解离速率常数（k（-0）= 0.00358 s（-1）），5c可以用作进一步阐明bc（1）功能机制的特异性探针，并作为未来药物发现的新的先导化合物。
Cytochrome bc(1) complex (EC 1.10.2.2, bc(1)), an essential component of the cellular respiratory chain and the photosynthetic apparatus in photosynthetic bacteria, has been identified as a promising target for new drugs and agricultural fungicides. X-ray diffraction structures of the free bc(1) complex and its complexes with various inhibitors revealed that the phenyl group of Phe274 in the binding pocket exhibited significant conformational flexibility upon different inhibitors binding to optimize respective pi-pi interactions, whereas the side chains of other hydrophobic residues showed conformational stability. Therefore, in the present study, a strategy of optimizing the pi-pi interaction with conformationally flexible residues was proposed to design and discover new bc(1) inhibitors with a higher potency. Eight new compounds were designed and synthesized, among which compound 5c, with a K(i) value of 570 pM, was identified as the most promising drug or fungicide candidate, significantly more potent than the commercially available bc(1) inhibitors, including azoxystrobin (AZ), kresoxim-methyl (KM), and pyraclostrobin (PY). To our knowledge, this is the first bc(1) inhibitor discovered from structure-based design with a potency of subnanomolar K(i) value. For all of the compounds synthesized and assayed, the calculated binding free energies correlated reasonably well with the binding free energies derived from the experimental K(i) values, with a correlation coefficient of r(2) = 0.89. The further inhibitory kinetics studies revealed that 5c is a noncompetitive inhibitor with respect to substrate cytochrome c, but it is a competitive inhibitor with respect to substrate ubiquinol. Due to its subnanomolar K(i) potency and slow dissociation rate constant (k(-0) = 0.00358 s(-1)), 5c could be used as a specific probe for further elucidation of the mechanism of bc(1) function and as a new lead compound for future drug discovery.
登录
查看更多内容
影响因子：
5
作者：
Luo, Cheng;Long, Jiangang;Liu, Jiankang
通讯作者：
Liu, Jiankang
影响因子：
2.9
作者：
Gao, XG;Wen, XL;Xia, D
通讯作者：
Xia, D
影响因子：
--
作者：
Froggett, JA;Hockley, MH;Titman, RB
通讯作者：
Titman, RB
影响因子：
4.1
作者：
Fisher, N;Meunier, B
通讯作者：
Meunier, B
DOI：
10.1111/j.1432-1033.2004.04036.x
发表时间：
2004-04-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Fisher, N;Bourges, I;Meunier, B
通讯作者：
Meunier, B