title: Rational design of an enzyme mutant for anti-cocaine therapeutics.
abstract: (-)-Cocaine is a widely abused drug and there is no available anti-cocaine therapeutic. The disastrous medical and social consequences of cocaine addiction have made the development of an effective pharmacological treatment a high priority. An ideal anti-cocaine medication would be to accelerate (-)-cocaine metabolism producing biologically inactive metabolites. The main metabolic pathway of cocaine in body is the hydrolysis at its benzoyl ester group. Reviewed in this article is the state-of-the-art computational design of high-activity mutants of human butyrylcholinesterase (BChE) against (-)-cocaine. The computational design of BChE mutants have been based on not only the structure of the enzyme, but also the detailed catalytic mechanisms for BChE-catalyzed hydrolysis of (-)-cocaine and (+)-cocaine. Computational studies of the detailed catalytic mechanisms and the structure-and-mechanism-based computational design have been carried out through the combined use of a variety of state-of-the-art techniques of molecular modeling. By using the computational insights into the catalytic mechanisms, a recently developed unique computational design strategy based on the simulation of the rate-determining transition state has been employed to design high-activity mutants of human BChE for hydrolysis of (-)-cocaine, leading to the exciting discovery of BChE mutants with a considerably improved catalytic efficiency against (-)-cocaine. One of the discovered BChE mutants (i.e., A199S/S287G/A328W/Y332G) has a approximately 456-fold improved catalytic efficiency against (-)-cocaine. The encouraging outcome of the computational design and discovery effort demonstrates that the unique computational design approach based on the transition-state simulation is promising for rational enzyme redesign and drug discovery.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 725 Rose Street, Lexington, KY, 40536, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Zheng
authors.forename: Chang-Guo
authors.initials: CG
authors.lastname: Zhan
mesh_terms: D002091:Butyrylcholinesterase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D002384:Catalysis; D003042:Cocaine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019970:Cocaine-Related Disorders / Q000188:drug therapy*; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D009154:Mutation
chemical_list: D002091:Butyrylcholinesterase; D003042:Cocaine