title: Most efficient cocaine hydrolase designed by virtual screening of transition states.
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.
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 725 Rose Street, Lexington, Kentucky 40536, USA.
authors: Fang
authors: F
authors: Zheng
authors: Wenchao
authors: W
authors: Yang
authors: Mei-Chuan
authors: MC
authors: Ko
authors: Junjun
authors: J
authors: Liu
authors: Hoon
authors: H
authors: Cho
authors: Daquan
authors: D
authors: Gao
authors: Min
authors: M
authors: Tong
authors: Hsin-Hsiung
authors: HH
authors: Tai
authors: James H
authors: JH
authors: Woods
authors: Chang-Guo
authors: CG
authors: Zhan
mesh_terms: D000818:Animals; D002091:Butyrylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D003042:Cocaine / Q000737:chemistry* / Q000378:metabolism; D003198:Computer Simulation; D015195:Drug Design; D006867:Hydrolases / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D051379:Mice; D008958:Models, Molecular; D011789:Quantum Theory; D013237:Stereoisomerism; D013816:Thermodynamics
chemical_list: D006867:Hydrolases; D002091:Butyrylcholinesterase; D003042:Cocaine