Computational Design of a Human Butyrylcholinesterase Mutant for Accelerating Cocaine Hydrolysis Based on the Transition-State

摘要

Cocaine is recognized as the most reinforcing of all drugs of abuse.[1]-[3] There is no available anticocaine medication. The disastrous medical and social consequences of cocaine addiction have made the development of an effective pharmacological treatment a high priority.[4]-[6] An ideal anticocaine medication would accelerate cocaine metabolism, thereby producing biologically inactive metabolites by a route similar to the primary cocaine-metabolizing pathway, that is, cocaine hydrolysis catalyzed by plasma enzyme butyrylcholinesterase (BChE).[5], [7]-[11] However, the native BChE has a low catalytic efficiency against naturally occurring (-)-cocaine.[12]-[15] (-)-Cocaine has a plasma half-life of 45-90 min, long enough for manifestation of the central nervous system (CNS) effects, which peak in minutes.[13], [16] Here we report an unconventional computational design that has led to the discovery of a human BChE mutant with a 151-fold improved catalytic efficiency; this mutant can be used as an exogenous enzyme in humans to prevent (-)-cocaine from reaching the CNS. The encouraging outcome not only provides a potential anticocaine medication but also demonstrates that a novel general approach of studying enzymatic mechanisms and computational drug design is promising.