The Importance of the Active Site Histidine for the Activity of Epoxide‐ or Aziridine‐Based Inhibitors of Cysteine Proteases
The Importance of the Active Site Histidine for the Activity of Epoxide‐ or Aziridine‐Based Inhibitors of Cysteine Proteases
复制标题
活性位点组氨酸对于基于环氧化物或氮丙啶的半胱氨酸蛋白酶抑制剂的活性的重要性
DOI：
10.1002/cmdc.200600159
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发表时间：
2007
期刊：
影响因子：
3.4
通讯作者：
B. Engels
中科院分区：
文献类型：
--
作者：
Milena Mladenović;T. Schirmeister;S. Thiel;W. Thiel;B. Engels
在本研究中，从理论上研究了活性位点组氨酸残基（His）对基于环氧化物或氮丙啶的半胱氨酸蛋白酶抑制剂活性的重要性。为了解释所有重要的影响，采用了QM/MM混合方法，该方法将描述键断裂和形成过程所需的联合收割机量子力学（QM）方法与结合蛋白质环境影响的分子力学（MM）方法相结合。使用不同的模型系统，计算排除了直接的质子转移从活性位点His残基的抑制剂，但显示，一个水分子是足够的，以建立一个非常有效的中继系统。该中继系统允许质子从活性位点His残基容易地转移到抑制剂，并且因此对于两种类型的抑制剂的活性是必不可少的。环氧化物和氮丙啶之间的差异进行了讨论，沿着优化抑制剂的合理设计的一些影响。本文介绍的工作代表了这些重要抑制剂类的作用模式的第一个QM/MM研究。
In the present study the importance of the active site histidine residue (His) for the activity of epoxide‐ or aziridine‐based cysteine protease inhibitors is examined theoretically. To account for all important effects, QM/MM hybrid approaches are employed which combine quantum mechanical (QM) methods that are necessary to describe bond‐breaking and formation processes, with molecular mechanics (MM) methods that incorporate the influence of the protein environment. Using various model systems, the computations exclude a direct proton shift from the active site His residue to the inhibitor, but show that one water molecule is sufficient to establish a very efficient relay system. This relay system allows an easy proton transfer from the active site His residue to the inhibitor and is thus essential for the activity of both types of inhibitors. Differences between the epoxides and the aziridines are discussed, along with some implications for the rational design of optimized inhibitors. The work presented herein represents the first QM/MM study into the mode of action of these important inhibitor classes.
影响因子：
7.3
作者：
Meara, JP;Rich, DH
通讯作者：
Rich, DH
影响因子：
15.9
作者：
ROSENTHAL, PJ;MCKERROW, JH;LEECH, JH
通讯作者：
LEECH, JH