First‐principle studies of intermolecular and intramolecular catalysis of protonated cocaine

Chen, Zhan; Deng, Shi‐Xian; Skiba, Jaime G.; Hayes, Beth A.; Tschampel, Sarah M.; Shields, George C.; Landry, Donald W.

doi:10.1002/jcc.20241

Cited by 53 publications

(59 citation statements)

References 66 publications

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“…[10][11][12] Cocaine is highly lipophilic, so much so that treatment of cocaine overdose includes the administration of lipid emulsions to dampen its effects. 13 Cocaine is also hydrophilic; the hydrochloride salt is readily soluble in aqueous solutions.…”

Section: Introductionmentioning

confidence: 99%

On the atomic structure of cocaine in solution

Johnston

Büsch

Pardo

et al. 2016

Phys. Chem. Chem. Phys.

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Cocaine is an amphiphilic drug which has the ability to cross the blood-brain barrier (BBB). Here, a combination of neutron diffraction and computation has been used to investigate the atomic scale structure of cocaine in aqueous solutions. Both the observed conformation and hydration of cocaine appear to contribute to its ability to cross hydrophobic layers afforded by the BBB, as the average conformation yields a structure which might allow cocaine to shield its hydrophilic regions from a lipophilic environment. Specifically, the carbonyl oxygens and amine group on cocaine, on average, form ∼5 bonds with the water molecules in the surrounding solvent, and the top 30% of water molecules within 4 Å of cocaine are localized in the cavity formed by an internal hydrogen bond within the cocaine molecule. This water mediated internal hydrogen bonding suggests a mechanism of interaction between cocaine and the BBB that negates the need for deprotonation prior to interaction with the lipophilic portions of this barrier. This finding also has important implications for understanding how neurologically active molecules are able to interact with both the blood stream and BBB and emphasizes the use of structural measurements in solution in order to understand important biological function.

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Section: Introductionmentioning

confidence: 99%

On the atomic structure of cocaine in solution

Johnston

Büsch

Pardo

et al. 2016

Phys. Chem. Chem. Phys.

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“…[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. There are some clear advantages of using this enzyme to accelerate the cocaine metabolism.…”

Section: Introductionmentioning

confidence: 99%

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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“…First-principles electronic structure calculations accounting for solvent effects have been carried out to study the detailed competing reaction pathways of the non-enzymatic hydrolysis of cocaine and the corresponding free energy barriers. The first-principles computational studies 32,36 have confirmed the co-existence of the competing reaction pathways. Below, we will only discuss the hydrolysis of cocaine at the benzoyl ester group (Fig.…”

Section: Hydrolysis Of Chair Cocainementioning

confidence: 81%

“…1). Based on the first-principles reaction coordinate calculations, 32 the optimized transition state geometry is shown in Fig. 3 as TS1-boat.…”

Section: Hydrolysis Of Boat Cocainementioning

confidence: 99%

“…Hence, a more complete understanding of the mechanism for cocaine hydrolysis in aqueous solution could provide valuable insights into the rational design of more effective transition-state analogs. This is why computational studies 32 for development of anti-cocaine catalytic antibodies have been focused on the reaction coordinate calculations on the detailed mechanisms for nonenzymatic hydrolysis of cocaine in water.…”

Section: Introductionmentioning

confidence: 99%

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Structure-and-mechanism-based design and discovery of therapeutics for cocaine overdose and addiction

Zheng

Chen

2008

Org. Biomol. Chem.

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Summary(−)-Cocaine is a widely abused drug and there is currently no available anti-cocaine therapeutic. Promising agents, such as anti-cocaine catalytic antibodies and high-activity mutants of human butyrylcholinesterase (BChE), for therapeutic treatment of cocaine overdose have been developed through the structure-and-mechanism-based design and discovery. In particular, a unique computational design strategy based on the modeling and simulation of rate-determining transition state has been developed and used to design and discover desirable high-activity mutants of BChE. One of the discovered high-activity mutants of BChE has a ~456-fold improved catalytic efficiency against (−)-cocaine. The encouraging outcome of the structure-and-mechanism-based design and discovery effort demonstrates that the unique computational design approach based on the transitionstate modeling and simulation is promising for rational enzyme redesign and drug discovery. The general approach of the structure-and-mechanism-based design and discovery may be used to design high-activity mutants of any enzyme or catalytic antibody.

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First‐principle studies of intermolecular and intramolecular catalysis of protonated cocaine

Cited by 53 publications

References 66 publications

On the atomic structure of cocaine in solution

On the atomic structure of cocaine in solution

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

Structure-and-mechanism-based design and discovery of therapeutics for cocaine overdose and addiction

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