EMBM - a new enzyme mechanism-based method for rational design of chemical sites of covalent inhibitors.
EMBM - a new enzyme mechanism-based method for rational design of chemical sites of covalent inhibitors.
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DOI：
10.1021/ci100330y
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发表时间：
2010-12-27
影响因子：
5.6
通讯作者：
Albeck, Amnon
中科院分区：
文献类型：
--
作者：
Traube, Tamar;Vijayakumar, Subramaniam;Hirsch, Michal;Uritsky, Neta;Shokhen, Michael;Albeck, Amnon
我们介绍了一种基于酶机制的方法EMBM，旨在合理设计反应配位类似物抑制剂的化学位点CS。由酶抑制剂共价复合物的形成引起的CS的价重组能由新的共价描述子W1和W2来解释。我们考虑了具有羰基反应中心的CS片段，就像天然蛋白酶底物一样。在模拟形成的共价四面体络合物-阴离子TC（O−）或中性TC（OH）的反应核心的小分子簇上，量子力学计算了W1和W2描述符。在反应核心上的建模允许生成各种CS和相应的TC（O−）和TC(OH)，作为真正抑制剂及其与丝氨酸或半胱氨酸水解酶的共价复合物的通用构建块。此外，该方法避免了对目标酶的三维结构的需要，因此EMBM可以用于基于配体的设计。我们建立了一个抑制剂的化学位点（CSI）数据库，为每个收集到的CS片段预先计算了ch30（−）和CH3S（−）亲核试剂的W1和W2描述符对。我们证明了CS片段对抑制剂结合亲和力的贡献取决于其在化学转化过程中的共价重组及其在酶活性位点的非共价相互作用。因此，只有考虑所有这些因素，使用W1和W2与非共价QSAR描述符结合，才能预测抑制剂的结合趋势。
We introduce an enzyme mechanism-based method, EMBM, aimed at rational design of chemical sites, CS, of reaction coordinate analog inhibitors. The energy of valence reorganization of CS, caused by the formation of the enzyme-inhibitor covalent complex, is accounted for by new covalent descriptors W1 and W2. We considered CS fragments with a carbonyl reactivity center, like in native protease substrates. The W1 and W2 descriptors are calculated quantum mechanically on small molecular clusters simulating the reaction core of the formed covalent tetrahedral complex – anionic TC(O−) or neutral TC(OH). The modeling on a reaction core allows generation of various CS and corresponding TC(O−) and TC(OH) as universal building blocks of real inhibitors and their covalent complexes with serine or cysteine hydrolases. Moreover, the approach avoids the need for 3D structure of the target enzyme, so EMBM may be used for ligand-based design. We have built a Chemical Site of Inhibitors (CSI) databank with pairs of W1 and W2 descriptors pre-calculated for both CH3O(−) and CH3S(−) nucleophiles for every collected CS fragment. We demonstrated that contribution of a CS fragment to the binding affinity of an inhibitor depends on both its covalent reorganization during the chemical transformation and its non-covalent interactions in the enzyme active site. Consequently, prediction of inhibitors binding trend can be done only by accounting for all of these factors, using W1 and W2 in combination with non-covalent QSAR descriptors.
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DOI：
10.1039/p29930000799
发表时间：
1993-05-01
期刊：
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 2
影响因子：
--
作者：
KLAMT, A;SCHUURMANN, G
通讯作者：
SCHUURMANN, G
影响因子：
15
作者：
CHRISTIANSON, DW;LIPSCOMB, WN
通讯作者：
LIPSCOMB, WN
影响因子：
3
作者：
MAPLE, JR;HWANG, MJ;HAGLER, AT
通讯作者：
HAGLER, AT
DOI：
10.1021/ci00020a020
发表时间：
1994-07-01
期刊：
JOURNAL OF CHEMICAL INFORMATION AND COMPUTER SCIENCES
影响因子：
--
作者：
ROGERS, D;HOPFINGER, AJ
通讯作者：
HOPFINGER, AJ
影响因子：
7.3
作者：
EDWARDS, PD;ZOTTOLA, MA;TUTHILL, PA
通讯作者：
TUTHILL, PA