ArticleMolecular pharmaceutics2018
Catalytic Reaction Mechanism for Drug Metabolism in Human Carboxylesterase-1: Cocaine Hydrolysis Pathway.
Article in Molecular pharmaceutics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 33 citations in OpenAlex.
- Experimental and In Silico Approaches to Study Carboxylesterase Substrate Specificity.Journal of xenobiotics · 2026Review
- In Silico Methodology for Human Carboxylesterases 1 and 2 Isoforms Substrate Selectivity Study.Methods in molecular biology (Clifton, N.J.) · 2026Article
- A quantitative LC-MS/MS method for investigation of polysubstance use involving heroin and cocaine.Journal of pharmaceutical and biomedical analysis · 2024Article
- Modeling onActa pharmaceutica Sinica. B · 2024Article
- Discovery of a novel homocysteine thiolactone hydrolase and the catalytic activity of its natural variants.Protein science : a publication of the Protein Society · 2024Article
- The reaction mechanism of the Ideonella sakaiensis PETase enzyme.Communications chemistry · 2024Article
- Catalytic activities of a highly efficient cocaine hydrolase for hydrolysis of biologically active cocaine metabolites norcocaine and benzoylecgonine.Scientific reports · 2023Article
- Convergence in determining enzyme functional descriptors across Kemp eliminase variants.Electronic structure (Bristol, England) · 2022Article
- Going deeper into the toxicokinetics of synthetic cannabinoids: in vitro contribution of human carboxylesterases.Archives of toxicology · 2022Article
- Catalytic Hydrolysis Mechanism of Cocaine by Human Carboxylesterase 1: An Orthoester Intermediate Slows Down the Reaction.Molecules (Basel, Switzerland) · 2019Article
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Authors and funding
4 authors at 1 institution in 2 countries.
Funding
Abstract
Carboxylesterase-1 (CE-1) is a crucial enzyme responsible for metabolism/activation/inactivation of xenobiotics (therapeutic agents, prodrugs, abused drugs, and organophosphorus nerve agents etc.) and also involved in many other biological processes. In this study, we performed extensive computational modeling and simulations to understand the fundamental reaction mechanism of cocaine hydrolysis catalyzed by CE-1, revealing that CE-1-catalyzed cocaine hydrolysis follows a novel reaction pathway with only two reaction steps: a single-step acylation process and a single-step deacylation process. In the transition states of both single-step processes, the cocaine NH group joins the oxyanion hole to form an additional hydrogen bond with the negatively charged carbonyl oxygen atom of the cocaine. Thus, the transition states are stabilized by both intermolecular and intramolecular hydrogen bonds with the methyl ester of cocaine, specifically the carbonyl oxygen atom. The rate-limiting transition state is associated with the acylation process, and the activation free energy barrier was predicted to be 20.1 kcal/mol. Further, in vitro experimental kinetic analysis was performed for human CE-1-catalyzed cocaine hydrolysis. For CE-1-catalyzed cocaine hydrolysis, the computationally predicted free energy barrier (20.1 kcal/mol) is reasonably close to the experimentally derived turnover number ( k
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