Zheng_2008_J.Am.Chem.Soc_130_12148

Reference

Title : Most efficient cocaine hydrolase designed by virtual screening of transition states - Zheng_2008_J.Am.Chem.Soc_130_12148
Author(s) : Zheng F , Yang W , Ko MC , Liu J , Cho H , Gao D , Tong M , Tai HH , Woods JH , Zhan CG
Ref : Journal of the American Chemical Society , 130 :12148 , 2008
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 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.
ESTHER : Zheng_2008_J.Am.Chem.Soc_130_12148
PubMedSearch : Zheng_2008_J.Am.Chem.Soc_130_12148
PubMedID: 18710224

Citations formats

Zheng F, Yang W, Ko MC, Liu J, Cho H, Gao D, Tong M, Tai HH, Woods JH, Zhan CG (2008)
Most efficient cocaine hydrolase designed by virtual screening of transition states
Journal of the American Chemical Society 130 :12148

Zheng F, Yang W, Ko MC, Liu J, Cho H, Gao D, Tong M, Tai HH, Woods JH, Zhan CG (2008)
Journal of the American Chemical Society 130 :12148