Mechanistic insights into a classic wonder drug--aspirin.
Mechanistic insights into a classic wonder drug--aspirin.
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DOI：
10.1021/ja5112964
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发表时间：
2015-01-14
影响因子：
15
通讯作者：
Zhang, Yingkai
中科院分区：
文献类型：
--
作者：
Lei, Jinping;Zhou, Yanzi;Xie, Daiqian;Zhang, Yingkai
阿司匹林是最古老和最常见的抗炎药之一，最近被证明可以降低癌症风险。阿司匹林的主要药理作用是通过Ser530的乙酰化作用对环氧合酶-2(COX-2)进行共价修饰，但其生化作用和特异性的详细机制仍有待阐明。在这项工作中，我们采用了最先进的计算方法，用从头算量子力学/分子力势的Born-Oppenheimer分子动力学模拟和伞形抽样来填补这一空白。我们的研究表征了底物辅助抑制阿司匹林乙酰化COX的机制：它分两个连续的阶段进行，中间体为亚稳的四面体中间体，其中阿司匹林的羧基作为一般碱。计算结果证实，阿司匹林对COX-1的抑制作用是对COX-2的10-100倍，并表明两种COX异构体之间的这种抑制特异性主要归因于共价抑制反应的动力学速率的差异，而不是阿司匹林结合步骤。阿司匹林对COX酶的这种差异性抑制的结构来源也被阐明。
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.
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影响因子：
15
作者：
Ke, Zhihong;Smith, Gregory K.;Zhang, Yingkai;Guo, Hua
通讯作者：
Guo, Hua
影响因子：
5.6
作者：
Gupta, K;Selinsky, BS;Loll, PJ
通讯作者：
Loll, PJ
DOI：
10.1073/pnas.97.2.925
发表时间：
2000-01-18
影响因子：
11.1
作者：
Kalgutkar, AS;Crews, BC;Marnett, LJ
通讯作者：
Marnett, LJ
影响因子：
5.5
作者：
Gumbart, James C.;Roux, Benoit;Chipot, Christophe
通讯作者：
Chipot, Christophe
影响因子：
4.8
作者：
Duggan, Kelsey C.;Walters, Matthew J.;Marnett, Lawrence J.
通讯作者：
Marnett, Lawrence J.