Cocaine is recognized as the most reinforcing one of widely abused drugs. There is no FDA-approved medication specific for cocaine. An ideal anti-cocaine medication would be to accelerate cocaine metabolism producing biologically inactive metabolites, via a route similar to the primary cocaine-metabolizing pathway, i.e. butyrylcholinesterase (BChE)-catalyzed hydrolysis. However, the native BChE has a low catalytic activity against the naturally occurring and biologically active (-)-cocaine. It is highly desirable to develop a BChE mutant with a significantly improved catalytic efficiency against (-)-cocaine.However, creation of a highly efficient enzyme for practical applications is a grand challenge. Compared to naturally occurring enzymes, computationally designed enzymes to date are much less efficient, with the catalytic activities being more than six orders of magnitude from the diffusion limit. In addition, only a small fraction of computational designs have even these very modest levels of catalytic activities, and the majority have no detectable activities. The low activities of computationally designed enzymes and the overall low design success rate are due to the limitation of popularly used computational design methods without a sophisticated approach to prediction of the catalytic activity. We have developed unique computational strategies and protocols based on the modeling and virtual screening of the transition-state structures of the enzymatic reactions. Using new computational enzyme design methods, we designed an extraordinarily efficient enzyme with the catalytic efficiency specific for cocaine hydrolysis comparable to that of the most efficient naturally occurring hydrolytic enzyme, i.e. acetylcholinesterase for neurotransmitter acetylcholine, with the catalytic activity approaching the diffusion limit.Acknowledgements  . This work was supported by the NIH (grants R01 DA035552, R01 DA032910, R01 DA013930, and R01 DA025100 to CGZ) and the NSF (grant CHE-1117671 to Zhan).

New computational approaches to design of a highly efficient therapeutic enzyme for treatment of cocaine abuse

246th National Meeting (2013)

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