Computational Discovery of Picomolar Qo Site Inhibitors of Cytochrome bc1 Complex
Computational Discovery of Picomolar Qo Site Inhibitors of Cytochrome bc1 Complex
复制标题
细胞色素 bc1 复合物皮摩尔 Q(o) 位点抑制剂的计算发现。
DOI：
10.1021/ja3001908
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发表时间：
2012-07-11
影响因子：
15
通讯作者：
Yang, Guang-Fu
中科院分区：
文献类型：
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作者：
Hao, Ge-Fei;Wang, Fu;Yang, Guang-Fu
由于基于生物物理方法的片段筛选的必要性，基于片段的药物发现(FBDD)面临的一个关键挑战是其低通量的性质。为此，成功建立了一种药效团连接片段虚拟筛选(PFVS)方法。它的应用产生了细胞色素BC(1)复合体的第一个皮摩尔范围Q(O)位抑制剂，细胞色素BC(1)复合体是药物和杀菌剂发现的重要膜蛋白。与最初的Hit化合物4(K-I=881.80 nM，猪BC(1))相比，最有效的化合物4f的结合亲和力提高了20507倍(K-I=43.00 pm)。化合物4f对底物细胞色素c是非竞争性抑制物，对底物泛喹酚是竞争性抑制物。此外，我们还测定了化合物4E(K-I=83.00 pm)在2.70埃分辨率下与鸡BC(1)结合的晶体结构，为理解其超效性提供了分子基础。据我们所知，这项研究是首次应用FBDD方法发现膜蛋白的皮摩尔抑制剂。这项工作表明，新的PFVS方法是一种独立于生物物理筛选技术的高通量药物发现方法。
A critical challenge to the fragment-based drug discovery (FBDD) is its low-throughput nature due to the necessity of biophysical method-based fragment screening. Herein, a method of pharmacophore-linked fragment virtual screening (PFVS) was successfully developed. Its application yielded the first picomolar-range Q(o) site inhibitors of the cytochrome bc(1) complex, an important membrane protein for drug and fungicide discovery. Compared with the original hit compound 4 (K-i = 881.80 nM, porcine bc(1)), the most potent compound 4f displayed 20 507-fold improved binding affinity (K-i = 43.00 pM). Compound 4f was proved to be a noncompetitive inhibitor with respect to the substrate cytochrome c, but a competitive inhibitor with respect to the substrate ubiquinol. Additionally, we determined the crystal structure of compound 4e (K-i = 83.00 pM) bound to the chicken bc(1) at 2.70 angstrom resolution, providing a molecular basis for understanding its ultrapotency. To our knowledge, this study is the first application of the FBDD method in the discovery of picomolar inhibitors of a membrane protein. This work demonstrates that the novel PFVS approach is a high-throughput drug discovery method, independent of biophysical screening techniques.