Lei Jinping, Zhou Yanzi, Xie Daiqian, Zhang Yingkai
Institute of Theoretical and Computational Chemistry, Laboratory of Mesoscopic Chemistry, School of Chemistry and Chemical Engineering, Nanjing University , Nanjing 210093, China.
J Am Chem Soc. 2015 Jan 14;137(1):70-3. doi: 10.1021/ja5112964. Epub 2014 Dec 22.
Aspirin, one of the oldest and most common anti-inflammatory agents, has recently been shown to reduce cancer risks. The principal pharmacological effects of aspirin are known to arise from its covalent modification of cyclooxygenase-2 (COX-2) through acetylation of Ser530, but the detailed mechanism of its biochemical action and specificity remains to be elucidated. In this work, we have filled this gap by employing a state-of-the-art computational approach, Born-Oppenheimer molecular dynamics simulations with ab initio quantum mechanical/molecular mechanical potential and umbrella sampling. Our studies have characterized a substrate-assisted inhibition mechanism for aspirin acetylating COX: it proceeds in two successive stages with a metastable tetrahedral intermediate, in which the carboxyl group of aspirin serves as the general base. The computational results confirmed that aspirin would be 10-100 times more potent against COX-1 than against COX-2, and revealed that this inhibition specificity between the two COX isoforms can be attributed mainly to the difference in kinetics rate of the covalent inhibition reaction, not the aspirin-binding step. The structural origin of this differential inhibition of the COX enzymes by aspirin has also been elucidated.
阿司匹林是最古老且最常用的抗炎药物之一，最近研究表明它能降低患癌风险。已知阿司匹林的主要药理作用源于其通过对Ser530进行乙酰化，对环氧合酶-2（COX-2）进行共价修饰，但其生化作用的详细机制和特异性仍有待阐明。在这项工作中，我们采用了先进的计算方法，即结合从头算量子力学/分子力学势的玻恩-奥本海默分子动力学模拟和伞形采样，填补了这一空白。我们的研究确定了阿司匹林乙酰化COX的底物辅助抑制机制：它分两个连续阶段进行，有一个亚稳态四面体中间体，其中阿司匹林的羧基充当广义碱。计算结果证实，阿司匹林对COX-1的效力比对COX-2强10至100倍，并表明这两种COX同工型之间的抑制特异性主要可归因于共价抑制反应动力学速率的差异，而非阿司匹林结合步骤。阿司匹林对COX酶这种差异抑制的结构根源也已阐明。
