Abstract
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.
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Abbreviations
- ACh:
-
Acetylcholine
- AChE:
-
Acetylcholinesterase
- BCh:
-
Butyrylcholine
- BChE:
-
Butyrylcholinesterase
- QM:
-
Quantum mechanics
- MM:
-
Molecular mechanics
- QM/MM:
-
Quantum mechanics/molecular mechanics
- MD:
-
Molecular dynamics
- BE:
-
Benzoylecgonine
- EME:
-
Ecgonine methyl ester
- CNS:
-
Central nervous system
- PET:
-
Positron emission tomography
- BAC2:
-
Base-catalyzed, acyl-oxygen cleavage, bimolecular
- IRC:
-
Intrinsic reaction coordinate
- TSA:
-
Transition state analog
- TS:
-
Transition state
- TS1:
-
Transition state for the first reaction step
- TS2:
-
Transition state for the second reaction step
- TS3:
-
Transition state for the third reaction step
- TS4:
-
Transition state for the fourth reaction step
- INT:
-
Intermediate
- INT1:
-
First intermediate
- INT2:
-
Second intermediate
- INT3:
-
Third intermediate
- ES:
-
Prereactive enzyme–substrate complex
- SCRF:
-
Self-consistent reaction field
- SVPE:
-
Surface and volume polarization for electrostatic interactions
- FPCM:
-
Fully polarizable continuum model
- PCM:
-
Polarizable continuum model
- HBR:
-
Hydrogen-bonded reactant complex
- NPA:
-
Natural population analysis
- HBE:
-
Hydrogen bonding energy
- 3D:
-
Three-dimensional
- ZPVE:
-
Zero-point vibration energy
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Acknowledgments
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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Zhan, CG. Modeling Reaction Mechanism of Cocaine Hydrolysis and Rational Drug Design for Therapeutic Treatment of Cocaine Abuse. In: Gupta, S.P. (eds) QSAR and Molecular Modeling Studies in Heterocyclic Drugs II. Topics in Heterocyclic Chemistry, vol 4. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7081_024
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DOI: https://doi.org/10.1007/7081_024
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