Department of Chemistry, The Skaggs Institute for Chemical Biology,The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
J Med Chem. 2010 Jan 14;53(1):230-40. doi: 10.1021/jm9012196.
Three cocrystal X-ray structures of the alpha-ketoheterocycle inhibitors 3-5 bound to a humanized variant of fatty acid amide hydrolase (FAAH) are disclosed and comparatively discussed alongside those of 1 (OL-135) and its isomer 2. These five X-ray structures systematically probe each of the three active site regions key to substrate or inhibitor binding: (1) the conformationally mobile acyl chain-binding pocket and membrane access channel responsible for fatty acid amide substrate and inhibitor acyl chain binding, (2) the atypical active site catalytic residues and surrounding oxyanion hole that covalently binds the core of the alpha-ketoheterocycle inhibitors captured as deprotonated hemiketals mimicking the tetrahedral intermediate of the enzyme-catalyzed reaction, and (3) the cytosolic port and its uniquely important imbedded ordered water molecules and a newly identified anion binding site. The detailed analysis of their key active site interactions and their implications on the interpretation of the available structure-activity relationships are discussed providing important insights for future design.
公开并比较了三种 α-酮杂环抑制剂 3-5 与人源化脂肪酸酰胺水解酶（FAAH）变体结合的共晶 X 射线结构，以及 1（OL-135）及其异构体 2 的结构。这五个 X 射线结构系统地探测了三个关键的活性位点区域中的每一个，这些区域对于底物或抑制剂结合至关重要：（1）构象灵活的酰基结合口袋和膜进入通道，负责脂肪酸酰胺底物和抑制剂酰基链结合，（2）非典型的活性位点催化残基和周围的氧阴离子穴，共价结合捕获的α-酮杂环抑制剂的核心，作为模拟酶催化反应的四面体中间物的去质子化半缩酮，以及（3）胞质腔及其独特的重要嵌入有序水分子和新鉴定的阴离子结合位点。讨论了它们关键的活性位点相互作用及其对现有结构-活性关系解释的影响，为未来的设计提供了重要的见解。
