Ma Zhiguo, Liu Hongming, Wu Baojian
Division of Pharmaceutics, College of Pharmacy, Jinan University, Guangzhou, Guangdong, China.
Br J Clin Pharmacol. 2014 Mar;77(3):410-20. doi: 10.1111/bcp.12169.
Catechol-O-methyltransferase (COMT) is of great importance in pharmacology because it catalyzes the metabolism (methylation) of endogenous and xenobiotic catechols. Moreover, inhibition of COMT is the drug target in the management of central nervous system (CNS) disorders such as Parkinson's disease due to its role in regulation of the dopamine level in the brain. The X-ray crystal structures for COMT have been available since 1994. The active sites for cofactor and substrate/inhibitor binding are well resolved to an atomic level, providing valuable insights into the catalytic mechanisms as well as the role of magnesium ions in catalysis. Determination of how the substrates/inhibitors bind to the protein leads to a structure-based approach that has resulted in potent and selective inhibitors. This review focuses on the design of two types of inhibitors (nitrocatechol-type and bisubstrate inhibitors) for COMT using the protein structures.
儿茶酚-O-甲基转移酶（COMT）在药理学中具有重要意义，因为它催化内源性和外源性儿茶酚的代谢（甲基化）。此外，由于COMT在调节大脑中多巴胺水平方面的作用，抑制COMT是治疗帕金森病等中枢神经系统（CNS）疾病的药物靶点。自1994年以来，已有COMT的X射线晶体结构。辅因子以及底物/抑制剂结合的活性位点已在原子水平上得到很好的解析，这为催化机制以及镁离子在催化中的作用提供了有价值的见解。确定底物/抑制剂如何与蛋白质结合导致了一种基于结构的方法，从而产生了强效和选择性抑制剂。本综述重点介绍了利用蛋白质结构设计的两类COMT抑制剂（硝基儿茶酚型和双底物抑制剂）。
