Most efficient cocaine hydrolase designed by virtual screening of transition states.

Journal of the American Chemical Society
Fang ZhengChang-Guo Zhan

Abstract

Cocaine is recognized as the most reinforcing of all drugs of abuse. There is no anticocaine medication available. The disastrous medical and social consequences of cocaine addiction have made the development of an anticocaine medication a high priority. It has been recognized that an ideal anticocaine medication is one that accelerates 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 an approximately 2000-fold improved catalytic efficiency, promising for therapeutic treatment of cocaine ov...Continue Reading

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Citations

Apr 10, 2010·Journal of Molecular Modeling·Steven Z FairchildWenling E Chang
Jun 16, 2012·Journal of the American Chemical Society·Donghui WeiChang-Guo Zhan
Aug 1, 2009·Journal of the American Chemical Society·Junjun LiuChang-Guo Zhan
Dec 24, 2010·The Journal of Physical Chemistry. B·Xi ChenChang-Guo Zhan
May 1, 2009·The Journal of Physical Chemistry. B·Yongmei PanChang-Guo Zhan
Oct 17, 2009·The Journal of Physical Chemistry. B·Xiaoqin HuangChang-Guo Zhan
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May 30, 2009·The Journal of Pharmacology and Experimental Therapeutics·Yang Gao, Stephen Brimijoin
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Mar 25, 2011·Future Medicinal Chemistry·Fang Zheng, Chang-Guo Zhan
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