Rational design of an enzyme mutant for anti-cocaine therapeutics

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26 Scopus citations


(-)-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 ∼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.

Original languageEnglish
Pages (from-to)661-671
Number of pages11
JournalJournal of Computer-Aided Molecular Design
Issue number9
StatePublished - 2008

Bibliographical note

Funding Information:
Acknowledgment Financial support from the National Institute on Drug Abuse (NIDA) of National Institutes of Health (NIH) (grant R01 DA013930) and extensive supercomputing time support from University of Kentucky Center of Computational Sciences are gratefully acknowledged.


  • Anti-cocaine medication
  • Cocaine abuse
  • Enzymatic reaction
  • Hydrolysis mechanism
  • Rational enzyme redesign
  • Transition state

ASJC Scopus subject areas

  • Drug Discovery
  • Computer Science Applications
  • Physical and Theoretical Chemistry


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