Most efficient cocaine hydrolase designed by virtual screening of transition states.
Most efficient cocaine hydrolase designed by virtual screening of transition states.
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DOI：
10.1021/ja803646t
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发表时间：
2008-09-10
影响因子：
15
通讯作者：
Zhan, Chang-Guo
中科院分区：
文献类型：
--
作者：
Zheng, Fang;Yang, Wenchao;Ko, Mei-Chuan;Liu, Junjun;Cho, Hoon;Gao, Daquan;Tong, Min;Tai, Hsin-Hsiung;Woods, James H.;Zhan, Chang-Guo
可卡因被认为是所有滥用药物中最具强化作用的药物。没有抗可卡因药物可用。可卡因成瘾造成的灾难性的医疗和社会后果使开发一种抗可卡因药物成为高度优先事项。它被认为是一种理想的抗可卡因药物，可以加速可卡因代谢，通过类似于可卡因主要代谢途径的途径，即由血浆酶丁酰胆碱酯酶（BChE）催化的可卡因水解，产生生物学上无活性的代谢物。然而，野生型BChE对滥用可卡因的催化效率较低。高活性酶突变体的设计是极具挑战性的，特别是当化学反应过程是酶促反应的速率决定因素时。在这里，我们报告的设计和发现的高活性突变体的人BChE通过使用一种新的，系统的计算设计方法的基础上过渡态模拟和活化能计算。新的计算设计方法已经导致发现最有效的可卡因水解酶，即具有102000倍改进的催化效率的人BChE突变体，有望作为外源酶用于治疗人类可卡因过量和成瘾。令人鼓舞的发现，从计算设计不仅提供了一个有前途的抗可卡因药物，但也表明，新的，普遍适用的计算设计方法是有希望的合理的酶的重新设计和药物发现。
Cocaine is recognized as the most reinforcing of all drugs of abuse. There is no anti-cocaine medication available. The disastrous medical and social consequences of cocaine addiction have made the development of an anti-cocaine medication a high priority. It has been recognized as an ideal anti-cocaine medication to accelerate cocaine metabolism producing biologically inactive metabolites via a route similar to the primary cocaine-metabolizing pathway, i.e. cocaine hydrolysis catalyzed by plasma enzyme butyrylcholinesterase (BChE). However, wild-type BChE has a low catalytic efficiency against the abused cocaine. Design of a high-activity enzyme mutant is extremely challenging, particularly when the chemical reaction process is rate determining for the enzymatic reaction. Here we report the design and discovery of a high-activity mutant of human BChE by using a novel, systematic computational design approach based on transition-state simulations and activation energy calculations. The novel computational design approach has led to discovery of the most efficient cocaine hydrolase, i.e. a human BChE mutant with a ∼2000-fold improved catalytic efficiency, promising for therapeutic treatment of cocaine overdose and addiction as an exogenous enzyme in human. The encouraging discovery resulted from the computational design not only provides a promising anti-cocaine medication, but also demonstrates that the novel, generally applicable computational design approach is promising for rational enzyme redesign and drug discovery.
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DOI：
10.1073/pnas.0403795101
发表时间：
2004-07-13
影响因子：
11.1
作者：
Carrera, MRA;Kaufmann, GF;Janda, KD
通讯作者：
Janda, KD
影响因子：
3.6
作者：
Gao, Y;Atanasova, E;Brimijoin, S
通讯作者：
Brimijoin, S
影响因子：
3.3
作者：
Gao, DQ;Zhan, CG
通讯作者：
Zhan, CG
DOI：
10.1073/pnas.0507332102
发表时间：
2005-11-15
影响因子：
11.1
作者：
Pan, YM;Gao, DQ;Zhan, CG
通讯作者：
Zhan, CG
DOI：
10.1038/nsb742
发表时间：
2002-01-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Larsen, NA;Turner, JM;Wilson, IA
通讯作者：
Wilson, IA