Chemistry, Design, and Structure−Activity Relationship of Cocaine Antagonists

Singh, Satendra

doi:10.1021/cr9700538

Cited by 259 publications

(243 citation statements)

References 345 publications

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“…ΔG E and ΔG TS1 were estimated by performing the FEP simulations in the present study. By using the calculated ΔΔG(1→2), the ratio of the catalytic efficiency associated with E(2) to that associated with E(1) can be evaluated, via (3) Equation (3) can also be used to derive the experimental ΔΔG(1→2) value from the experimental ratio of the catalytic efficiency associated with E(2) to that associated with E(1).…”

Section: Free Energy Simulationmentioning

confidence: 99%

“…[1][2][3] The disastrous medical and social consequences of cocaine addiction have made the development of an effective pharmacological treatment a high priority. [4][5][6] It is commonly believed that cocaine mediates its reinforcing and toxic effects by blocking neurotransmitter reuptake in the central nervous system (CNS).…”

Section: Introductionmentioning

confidence: 99%

“…However, the classical pharmacodynamic approach, which means to design small molecules to target the related transporters or receptors in CNS, has failed to yield a really useful antagonist due to the difficulties inherent in blocking a blocker. [1][2][3][4]6 An alternative approach is to interfere with the delivery of cocaine to its receptors or accelerate its metabolism in the body. 4,[7][8][9][10][11][12][13][14][15][16][17] Butyrylcholinesterase (BChE), the principal plasma enzyme that catalyzes cocaine hydrolysis into its biologically inactive metabolites, is an ideal target for this purpose.…”

Section: Introductionmentioning

confidence: 99%

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Free Energy Perturbation (FEP) Simulation on the Transition States of Cocaine Hydrolysis Catalyzed by Human Butyrylcholinesterase and Its Mutants

et al. 2007

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A novel computational protocol based on free energy perturbation (FEP) simulations on both the free enzyme and transition state structures has been developed and tested to predict the mutation-caused shift of the free energy change from the free enzyme to the rate-determining transition state for human butyrylcholinesterase (BChE)-catalyzed hydrolysis of (-)-cocaine. The calculated shift, denoted by ΔΔG(1→2), of such kind of free energy change determines the catalytic efficiency (k cat /K M ) change caused by the simulated mutation transforming enzyme 1 to enzyme 2. By using the FEP-based computational protocol, the ΔΔG(1→2) values for the mutations A328W/Y332A → A328W/Y332G and A328W/Y332G → A328W/Y332G/A199S were calculated to be -0.22 and -1.94 kcal/mol, respectively. The calculated ΔΔG(1→2) values predict that the change from the A328W/Y332A mutant to the A328W/Y332G mutant should slightly improve the catalytic efficiency and that the change from the A328W/Y332G mutant to the A328W/Y332G/A199S mutant should significantly improve the catalytic efficiency of the enzyme for the (-)-cocaine hydrolysis. The predicted catalytic efficiency increases are supported by the experimental data showing that k cat /K M = 8.5 × 10 6 , 1.4 × 10 7 , and 7.2 × 10 7 min -1 M -1 for the A328W/Y332A, A328W/Y332G, and A328W/Y332G/A199S mutants, respectively. The qualitative agreement between the computational and experimental data suggests that the FEP simulations may provide a promising protocol for rational design of highactivity mutants of an enzyme. The general computational strategy of the FEP simulation on a transition state can be used to study the effects of a mutation on the activation free energy for any enzymatic reaction.

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Section: Free Energy Simulationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Free Energy Perturbation (FEP) Simulation on the Transition States of Cocaine Hydrolysis Catalyzed by Human Butyrylcholinesterase and Its Mutants

et al. 2007

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“…As many as over 300 cocaine derivatives have been synthesised and characterised by determining their in vitro binding affinity to the monoamine transporters (Singh 2000). A number of different radiolabelled (e.g.…”

Section: Dopamine Transporter In Vitro Bindingmentioning

confidence: 99%

Dopamine Transporter in vitro Binding and in vivo Imaging in the Brain

Bergström¹,

Tupala²,

Tiihonen³

2001

Pharmacology & Toxicology

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Much research interest has lately been focused on the dopamine transporter function in brain. Recent findings indicate that dopamine reuptake is more like a highly regulated than a constitutive determinant of dopamine clearance. Positron emission tomography (PET) and single-photon emission tomography (SPET) offer unique methods to study dopamine transporter function. Results from in vivo PET and SPET studies correspond well with in vitro studies performed on post mortem human brain tissue. Considering some of the variances between in vitro and in vivo receptor binding phenomena it may be that the role of a compound to alter binding to monoamine uptake sites in vitro does not indicate its potential to affect monoamine transporters after administration in vivo. This discrepancy may be better understood taking into account recent studies indicating the possibility of a rapid regulation of transporter function and surface expression. Furthermore, the dopamine transporter is a fruitful target for CNS drug discovery. Fundamental nature of drug actions in vivo may be studied using demonstrated in vitro and in vivo imaging methods.

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“…Cocaine is the most reinforcing of all drugs of abuse. 1,2,3 The disastrous medical and social consequences of cocaine addiction have made the development of an anti-cocaine medication a high priority. 4,5,6,7,8,9,10,11,12,13,14 The alkaloid nicotine (12), initially found in tobacco leaves, is the addictive amine compound that maintains tobacco smoking behavior.…”

Section: Introductionmentioning

confidence: 99%

First-Principles Calculation of pK_a for Cocaine, Nicotine, Neurotransmitters, and Anilines in Aqueous Solution

Chen

2007

J. Phys. Chem. B

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The absolute pK a values of 24 representative amine compounds, including cocaine, nicotine, 10 neurotransmitters, and 12 anilines, in aqueous solution were calculated by performing first-principles electronic structure calculations that account for the solvent effects using four different solvation models, i.e. the surface and volume polarization for electrostatic interaction (SVPE) model, the standard polarizable continuum model (PCM), the integral equation formalism for the polarizable continuum model (IEFPCM), and the conductor-like screening solvation model (COSMO). Within the examined computational methods, the calculations using the SVPE model lead to the absolute pK a values with the smallest root-mean-square-deviation (RMSD) value (1.18). When the SVPE model was replaced by the PCM, IEFPCM, and COSMO, the RMSD value of the calculated absolute pK a values became 3.21, 2.72, and 3.08, respectively. All types of calculated pK a values linearly correlate with the experimental pK a values very well. With the empirical corrections using the linear correlation relationships, the theoretical pK a values are much closer to the corresponding experimental data and the RMSD values become 0.51 to 0.83. The smallest RMSD value (0.51) is also associated with the SVPE model. All of the results suggest that the first-principles electronic structure calculations using the SVPE model are a reliable approach to the pK a prediction for the amine compounds.

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Chemistry, Design, and Structure−Activity Relationship of Cocaine Antagonists

Cited by 259 publications

References 345 publications

Free Energy Perturbation (FEP) Simulation on the Transition States of Cocaine Hydrolysis Catalyzed by Human Butyrylcholinesterase and Its Mutants

Free Energy Perturbation (FEP) Simulation on the Transition States of Cocaine Hydrolysis Catalyzed by Human Butyrylcholinesterase and Its Mutants

Dopamine Transporter in vitro Binding and in vivo Imaging in the Brain

First-Principles Calculation of pK_a for Cocaine, Nicotine, Neurotransmitters, and Anilines in Aqueous Solution

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Chemistry, Design, and Structure−Activity Relationship of Cocaine Antagonists

Cited by 259 publications

References 345 publications

Free Energy Perturbation (FEP) Simulation on the Transition States of Cocaine Hydrolysis Catalyzed by Human Butyrylcholinesterase and Its Mutants

Free Energy Perturbation (FEP) Simulation on the Transition States of Cocaine Hydrolysis Catalyzed by Human Butyrylcholinesterase and Its Mutants

Dopamine Transporter in vitro Binding and in vivo Imaging in the Brain

First-Principles Calculation of pKa for Cocaine, Nicotine, Neurotransmitters, and Anilines in Aqueous Solution

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Product

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First-Principles Calculation of pK_a for Cocaine, Nicotine, Neurotransmitters, and Anilines in Aqueous Solution