Document Detail

Most efficient cocaine hydrolase designed by virtual screening of transition states.
MedLine Citation:
PMID:  18710224     Owner:  NLM     Status:  MEDLINE    
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 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.
Fang Zheng; Wenchao Yang; Mei-Chuan Ko; Junjun Liu; Hoon Cho; Daquan Gao; Min Tong; Hsin-Hsiung Tai; James H Woods; Chang-Guo Zhan
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2008-08-19
Journal Detail:
Title:  Journal of the American Chemical Society     Volume:  130     ISSN:  1520-5126     ISO Abbreviation:  J. Am. Chem. Soc.     Publication Date:  2008 Sep 
Date Detail:
Created Date:  2008-09-03     Completed Date:  2008-10-21     Revised Date:  2014-09-13    
Medline Journal Info:
Nlm Unique ID:  7503056     Medline TA:  J Am Chem Soc     Country:  United States    
Other Details:
Languages:  eng     Pagination:  12148-55     Citation Subset:  IM    
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MeSH Terms
Butyrylcholinesterase / chemistry*,  metabolism
Cocaine / chemistry*,  metabolism
Computer Simulation
Drug Design*
Hydrolases / chemistry*,  metabolism,  pharmacology
Models, Molecular
Quantum Theory
Grant Support
DA013930/DA/NIDA NIH HHS; DA021416/DA/NIDA NIH HHS; R01 DA013930/DA/NIDA NIH HHS; R01 DA013930-05/DA/NIDA NIH HHS; R01 DA013930-06/DA/NIDA NIH HHS; R01 DA013930-06S1/DA/NIDA NIH HHS; R01 DA021416/DA/NIDA NIH HHS; R01 DA021416-03/DA/NIDA NIH HHS
Reg. No./Substance:
EC 3.-/Hydrolases; EC 3.1.1.-/Butyrylcholinesterase; I5Y540LHVR/Cocaine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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