| Most efficient cocaine hydrolase designed by virtual screening of transition states. | |
| | |
MedLine Citation:
|
PMID: 18710224 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
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. |
| | |
Authors:
|
Fang Zheng; Wenchao Yang; Mei-Chuan Ko; Junjun Liu; Hoon Cho; Daquan Gao; Min Tong; Hsin-Hsiung Tai; James H Woods; Chang-Guo Zhan |
Related Documents
:
|
7719784 - Standards for medical identifiers, codes, and messages needed to create an efficient co... 15212594 - Genosense diagnostics gmbh. 11187644 - Knowledge engineering the umls. 2886294 - A vocabulary for medical informatics. 12190234 - Self-medication with gamma-hydroxybutyrate to reduce alcohol intake. 8600424 - Schnyder crystalline dystrophy sine crystals. recommendation for a revision of nomencla... |
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: 2011-05-16 |
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 |
Affiliation:
|
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 725 Rose Street, Lexington, Kentucky 40536, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Animals Butyrylcholinesterase / chemistry*, metabolism Cocaine / chemistry*, metabolism Computer Simulation Drug Design* Hydrolases / chemistry*, metabolism, pharmacology Kinetics Male Mice Models, Molecular Quantum Theory Stereoisomerism Thermodynamics |
| Grant Support | |
ID/Acronym/Agency:
|
DA013930/DA/NIDA NIH HHS; DA021416/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 DA021416-03/DA/NIDA NIH HHS |
| Chemical | |
Reg. No./Substance:
|
50-36-2/Cocaine; EC 3.-/Hydrolases; EC 3.1.1.-/Butyrylcholinesterase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Harnessing scorpionate ligand equilibria for modeling reduced nickel superoxide dismutase intermedia...
Next Document: Nanoparticle-mediated intervalence transfer.