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

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QSAR and Molecular Modeling Studies in Heterocyclic Drugs II

Part of the book series: Topics in Heterocyclic Chemistry ((TOPICS,volume 4))

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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  1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 725 Rose Street, 40536, Lexington, KY, USA

    Chang-Guo Zhan

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  1. Chang-Guo Zhan
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Correspondence to Chang-Guo Zhan .

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Satya Prakash Gupta

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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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