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Most Efficient Cocaine Hydrolase Designed by Virtual Screening of Transition States
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Hi-Res PDFUniversity of Kentucky.
, ‡University of Michigan Medical School.
Section: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 
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 anticocaine 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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This article has been cited by 16 ACS Journal articles (5 most recent appear below).
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Reaction Mechanism for Cocaine Esterase-Catalyzed Hydrolyses of (+)- and (−)-Cocaine: Unexpected Common Rate-Determining Step
Junjun Liu, Xinyun Zhao, Wenchao Yang, and Chang-Guo ZhanThe Journal of Physical Chemistry B2011 Article ASAPReaction Mechanism for Cocaine Esterase-Catalyzed Hydrolyses of (+)- and (−)-Cocaine: Unexpected Common Rate-Determining Step
Junjun Liu, Xinyun Zhao, Wenchao Yang, and Chang-Guo ZhanThe Journal of Physical Chemistry B2011 Article ASAPFirst-principles quantum mechanical/molecular mechanical free energy calculations have been performed to examine the catalytic mechanism for cocaine esterase (CocE)-catalyzed hydrolysis of (+)-cocaine in comparison with CocE-catalyzed hydrolysis of (−)-...
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- Published In Issue September 10, 2008
- Article ASAPAugust 19, 2008
- Received: May 16, 2008
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