Substrate-assisted antibody catalysis

Deng, Shi‐Xian; Bharat, Narine; Prada, Paloma de; Landry, Donald W.

doi:10.1039/b314264g

Cited by 6 publications

(3 citation statements)

References 13 publications

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“…Such a TSA structure (depicted in Chart ) was synthesized and 85 cocaine esterases out of 450 antianalog antibodies were elicited—a performance markedly superior to that of a previously employed simple phosphonate ester as a stable analog of the transition state structure for the benzoyl ester hydrolysis of chair cocaine 6, 7, 9. In turn, the encouraging experimental results13 support the thrust of these computations.…”

Section: Resultssupporting

confidence: 56%

“…Here we report the computational studies, whereas the corresponding experimental studies have been reported elsewhere (the computational studies described in this report were actually completed far before the experimental studies described in ref. 13, but the submission of this report for publication was delayed consideralby due to some unexpected reason) 13…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2005

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We have performed a series of first-principles electronic structure calculations to examine the reaction pathways and the corresponding free energy barriers for the ester hydrolysis of protonated cocaine in its chair and boat conformations. The calculated free energy barriers for the benzoyl ester hydrolysis of protonated chair cocaine are close to the corresponding barriers calculated for the benzoyl ester hydrolysis of neutral cocaine. However, the free energy barrier calculated for the methyl ester hydrolysis of protonated cocaine in its chair conformation is significantly lower than for the methyl ester hydrolysis of neutral cocaine and for the dominant pathway of the benzoyl ester hydrolysis of protonated cocaine. The significant decrease of the free energy barrier, ~ 4 kcal/mol, is attributed to the intramolecular acid catalysis of the methyl ester hydrolysis of protonated cocaine, because the transition state structure is stabilized by the strong hydrogen bond between the carbonyl oxygen of the methyl ester moiety and the protonated tropane N. The relative magnitudes of the free energy barriers calculated for different pathways of the ester hydrolysis of protonated chair cocaine are consistent with the experimental kinetic data for cocaine hydrolysis under physiologic conditions. Similar intramolecular acid catalysis also occurs for the benzoyl ester hydrolysis of (protonated) boat cocaine in the physiologic condition, although the contribution of the intramolecular hydrogen bonding to transition state stabilization is negligible. Nonetheless, the predictability of the intramolecular hydrogen bonding could be useful in generating antibody-based catalysts that recruit cocaine to the boat conformation and an analog that elicited antibodies to approximate the protonated tropane N and the benzoyl O more closely than the natural boat conformer might increase the contribution from hydrogen bonding. Such a stable analog of the transition state for intramolecular catalysis of cocaine benzoyl-ester hydrolysis was synthesized and used to successfully elicit a number of anti-cocaine catalytic antibodies.

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Section: Resultssupporting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

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

et al. 2005

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“…These studies have used other TSAs, but, so far, the catalytic antibodies produced have had K m values in the millimolar range and/or K cat values well below 1 min −1 [37–40]. Attempts to mutate previously identified cocaine catalytic antibodies have not been any more successful [41].…”

Section: Cocaine Catalytic Antibodiesmentioning

confidence: 99%

Accelerating Cocaine Metabolism as an Approach to the Treatment of Cocaine Abuse and Toxicity

Schindler

Goldberg

2012

Future Med. Chem.

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One pharmacokinetic approach to the treatment of cocaine abuse and toxicity involves the development of compounds that can be safely administered to humans and that accelerate the metabolism of cocaine to inactive components. Catalytic antibodies have been developed and shown to accelerate cocaine metabolism, but their catalytic efficiency for cocaine is relatively low. Mutations of human butyrylcholinesterase and a bacterial cocaine esterase found in the soil of coca plants have also been developed. These compounds accelerate cocaine metabolism and antagonize the behavioral and toxic effects of cocaine in animal models. Of these two approaches, the human butyrylcholinesterase mutants show the most immediate promise as they would not be expected to evoke an immune response in humans.

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Survey of the year 2004 commercial optical biosensor literature

Rich

Myszka

2005

J of Molecular Recognition

115

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The year 2004 represents a milestone for the biosensor research community: in this year, over 1000 articles were published describing experiments performed using commercially available systems. The 1038 papers we found represent a $ 10% increase over the past year and demonstrate that the implementation of biosensors continues to expand at a healthy pace. We evaluated the data presented in each paper and compiled a 'top 10' list. These 10 articles, which we recommend every biosensor user reads, describe wellperformed kinetic, equilibrium and qualitative/screening studies, provide comparisons between binding parameters obtained from different biosensor users, as well as from biosensor-and solution-based interaction analyses, and summarize the cutting-edge applications of the technology. We also re-iterate some of the experimental pitfalls that lead to sub-optimal data and over-interpreted results. We are hopeful that the biosensor community, by applying the hints we outline, will obtain data on a par with that presented in the 10 spotlighted articles. This will ensure that the scientific community at large can be confident in the data we report from optical biosensors.

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Substrate-assisted antibody catalysis

Cited by 6 publications

References 13 publications

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

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

Accelerating Cocaine Metabolism as an Approach to the Treatment of Cocaine Abuse and Toxicity

Survey of the year 2004 commercial optical biosensor literature

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