Modeling Reaction Mechanism of Cocaine Hydrolysis and Rational Drug Design for Therapeutic Treatment of Cocaine Abuse

  • Chang-Guo ZhanEmail author
Part of the Topics in Heterocyclic Chemistry book series (TOPICS, volume 4)


Cocaine is a widely abused heterocyclic 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 accelerate cocaine metabolism producing biologically inactive metabolites. The main metabolic pathway of cocaine in the body is hydrolysis at its benzoyl ester group. State-of-the-art molecular modeling of the reaction mechanism for the hydrolysis of cocaine and the mechanism-based design of anti-cocaine therapeutics will be discussed. First of all, competing reaction pathways and the transition state stabilization of the spontaneous hydrolysis of cocaine in solution will be examined. It will be demonstrated that the information obtained about the transition states and their stabilization has been very useful in the rational design of stable analogs of the transition states of cocaine hydrolysis, in order to elicit anti-cocaine catalytic antibodies. Detailed molecular modeling of the reaction mechanism for cocaine hydrolysis catalyzed by human butyrylcholinesterase (BChE), the primary cocaine-metabolizing enzyme in body, will be examined. Then, we will describe the application of these mechanistic insights to the rational design of human BChE mutants as a new therapeutic treatment of cocaine abuse. Finally, future directions of the mechanism-based design of anti-cocaine therapeutics will be discussed.

Cocaine Hydrolysis mechanism Transition-state simulation Rational enzyme redesign Catalytic antibody 











Quantum mechanics


Molecular mechanics


Quantum mechanics/molecular mechanics


Molecular dynamics




Ecgonine methyl ester


Central nervous system


Positron emission tomography


Base-catalyzed, acyl-oxygen cleavage, bimolecular


Intrinsic reaction coordinate


Transition state analog


Transition state


Transition state for the first reaction step


Transition state for the second reaction step


Transition state for the third reaction step


Transition state for the fourth reaction step




First intermediate


Second intermediate


Third intermediate


Prereactive enzyme–substrate complex


Self-consistent reaction field


Surface and volume polarization for electrostatic interactions


Fully polarizable continuum model


Polarizable continuum model


Hydrogen-bonded reactant complex


Natural population analysis


Hydrogen bonding energy




Zero-point vibration energy


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The financial support from the National Institute on Drug Abuse (NIDA) of the National Institutes of Health (NIH) (grant R01 DA013930) is gratefully acknowledged.


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Authors and Affiliations

  1. 1.Department of Pharmaceutical Sciences, College of PharmacyUniversity of KentuckyLexingtonUSA

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