Study of substrate selectivity of Carboxylesterases with biopharmaceutical relevance

RIBONE, S.R.; ESTRIN, D.; QUEVEDO, M.A.

Congreso; Reunión Internacional de Ciencias Farmacéuticas (RiCiFa-2021); 2021

Carboxylesterases subtypes, CES1 and CES2, are involved in the metabolism andbioactivation of drugs and prodrugs. Although previous reports described structural specificity of the different CES subtypes towards their substrate, the molecular basis behind this selectivity remains unclear. The objective of this work is focused on the exploration of the atomistic details related to this molecular specificity, using a combination of molecular modeling strategies on three esters of p-nitrophenol containing different substituents. First, molecular docking studies were performed onthe catalytic site of both CES, using DOCK6 software. Second, molecular dynamic simulations wereperformed on the obtained ligand-enzyme complexes. Finally, hybrid QM/MM simulations wereperformed on all the complexes, using Amber18 software package. Results obtained from theQM/MM simulation showed that the dealkylation was the limiting step on the enzymatic hydrolysis.In addition, the ΔG obtained displayed the same order of magnitude as the previously reported kcat for the hydrolysis for these esters on both CES. In conclusion, the molecular modeling proceduredeveloped in this work was able to reproduce the trend in the hydrolysis of three different esters ofp-nitrophenol by CES1 and 2, constituting a crucial key for the study of CES selectivity on newselected substrates.