阿司匹林抑制环氧合酶的内在机理
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- 英文论文题名：Biochemical Inner Workings of Aspirin Modifying Cyclooxygenase
- 论文作者：周燕子 ; 雷金平 ; 谢代前 ; 张颖凯
- 英文论文作者：Yanzi Zhou ; Jinping Lei ; Daiqian Xie ; Yingkai Zhang ; Institute of Theoretical and Computational Chemistry ; School of Chemistry and Chemical Engineering ; Nanjing University ; Department of Chemistry ; New York University
- 年：2016
- 作者机构：南京大学化学化工学院理论与计算化学研究所;纽约大学化学系;
- 论文关键词：共价抑制剂 ; 选择性 ; 量子力学/分子力学动力学模拟
- 会议召开时间：2016-07-01
- 会议录名称：中国化学会第30届学术年会摘要集-第十九分会：化学中的量子与经典动力学
- 语种：中文
- 分类号：R96
- 学会代码：ZGHY
- 会议名称：中国化学会第30届学术年会-第十九分会 ; 化学中的量子与经典动力学
- 会议地点：中国辽宁大连
- 主办单位：中国化学会
- 学会名称：中国化学会
- 页数：1
- 文件大小：143k
- 原文格式：D
- 会议级别：全国
摘要
环氧合酶主要有COX-1和COX-2两种同工酶:COX-1是正常的酶;COX-2是诱导酶,由它生成的前列腺素会导致炎症,疼痛,发烧等病症,它是重要的药物靶标。阿司匹林是目前唯一用于临床的共价消炎药,但是它并没有COX-2选择性,它抑制COX-1比抑制COX-2更强,将产生消化性溃疡和消化不良等副作用。然而阿司匹林在整个药物市场都占有很大的比例,所以寻找阿司匹林的替代物是近年来的重要课题之一。我们采用Born-Oppenheimer从头算量子力学/分子力学动力学模拟方法 (QM/MM-MD)研究了阿司匹林抑制环氧合酶的具体机理。计算结果表明阿司匹林之所以抑制COX-1更强主要在于它与COX-1的共价结合的反应速率更快。通过进一步的残基分析,发现了影响抑制能力的重要的残基His(COX1)/Arg(COX2)513,而阿司匹林的羧基与这两个残基的作用不同是抑制能力差异的来源;提出了去除阿司匹林的羧基可能提高药物的选择性,这对于设计具有COX-2高选择性的类阿司匹林药物有着重要的指导意义。
COX has two isoforms: COX-1 is the constitutively expressed isoform; COX-2 functions mainly in acute or pathophysiological responses. Aspirin is the only clinical covalent anti-inflammatory drug inhibiting COX permanently, but its lack of COX-2 selectivity causes a series of side effects. The search for super-aspirins is one important project of recent years. By employing QM/MM-MD method, we studied the detailed mechanism about how aspirin inhibits COX, which revealed that this inhibition specificity mainly comes from the difference in kinetics rate of the covalent inhibition reaction. Our analysis indicates that Arg513 in COX-2 would increase the activation barrier of acetylation reaction, while the corresponding His513 in COX-1 plays almost no role, which is consistent with experimental results that the derivatization of the carboxylate moiety of aspirin can always increase the COX-2 selectivity. These findings might throw light on the design of high COX-2 selectivity aspirin-like molecules.
COX has two isoforms: COX-1 is the constitutively expressed isoform; COX-2 functions mainly in acute or pathophysiological responses. Aspirin is the only clinical covalent anti-inflammatory drug inhibiting COX permanently, but its lack of COX-2 selectivity causes a series of side effects. The search for super-aspirins is one important project of recent years. By employing QM/MM-MD method, we studied the detailed mechanism about how aspirin inhibits COX, which revealed that this inhibition specificity mainly comes from the difference in kinetics rate of the covalent inhibition reaction. Our analysis indicates that Arg513 in COX-2 would increase the activation barrier of acetylation reaction, while the corresponding His513 in COX-1 plays almost no role, which is consistent with experimental results that the derivatization of the carboxylate moiety of aspirin can always increase the COX-2 selectivity. These findings might throw light on the design of high COX-2 selectivity aspirin-like molecules.
引文
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[2]Mitchell,J.A.;Akarasereenont,P.;Thiemermann,C.;Flower,R.J.;Vane,J.R.Proc.Natl.Acad.Sci.U.S.A.1993,90:11693.