Year: 2021
Type: article
Abstract: Increased hydrolysis of cocaine to non-toxic compounds is a promising way to prevent cocaine-induced toxicity. However, the short half-life of cocaine in the blood and the rapid conversion in the body to the hydrolysis-resistant metabolite benzoylecgonine, limits the therapeutic potential of serum proteins. Therefore, hydrolysis by tissue-specific hydrolases that do not generate benzoylecgonine deserves further investigation. Here, we report for the first time, the mechanism of cocaine hydrolysis by the human Carboxylesterase 2. We have combined conventional and accelerated Molecular Dynamics, which allowed us to identify the structural motions of the α1 and α10’ helices that act as a putative lid. Quantum Mechanics/Molecular Mechanics calculations on the full cycle showed that the rate-limiting step is the formation of benzoic acid (deacylation step) with an ΔG of 18.3 kcal.mol-1 (a value in close conformity with the experimental value of 19.7 kcal.mol-1).
Source: Molecular Catalysis
Institutions: University of Coimbra, Almac (United Kingdom)
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: bronze
Awards: G14729215, G1504391740, G1577006909, Role of metal ions in DNA recognition by proteins, G2127175253, Enzymatic synthesis of RNA-peptide conjugates as potential therapeutics for Covid-19, G3864332066, G4015828041, G5076359958, Centro de Inovação em Biomedicina e Biotecnologia, G7082142669, Enzymatic synthesis of biodegradable amphiphilic polymer-drugs for cancer treatment, G7965203573, G7991599336
OpenAlex ID: W3204987835