Desenvolvimento de modelos empíricos de predição da atividade de inibidores da enzima acetilcolinesterase de Torpedo californica e de Aedes aegypti utilizando o método semi-empírico

Abstract

Acetylcholinesterase (AChE) is an enzyme essential for the central and peripheral cholinergic transmission. AChE inhibitors can be applied as medicines and they are the principal compounds used nowadays for the treatment of Alzheimer’s disease (AD). AD is a neurodegenerative disorder, which presents an important socio-economic impact, responsible for 50-60% of the total number of dementia cases among people above 65-years old. Although irreversible AChE inhibitors are not commonly used as medicines for humans, their use is common for the control of disease vectors, especially diseases transmitted by mosquitos, such as dengue fever. The World Health Organization (WHO) estimates that 50-100 million people are infected by the dengue virus annually in 100 countries. The objective of the present work is the development of empirical models for prediction of the activities of synthetic compounds as inhibitors of AChE. The models were based on activity data for the inhibition of Torpedo californica AChE by mesoionic compounds and harmane derivatives, synthesized by research groups from UFRRJ, and bivalent β-carbolines, obtained from the literature. The same procedure was applied to the development of an empirical model for the prediction of bivalent β-carbolines inhibition data of Aedes aegypti AChE. The complete procedure involved the use of the molecular docking procedure for the generation of ligands/enzyme complexes, followed by calculations of the interaction enthalpies in the gas phase by semi-empirical methods. For the study with the Aedes aegypti AChE, it was necessary the previous construction of a comparative model of the enzyme’s 3D structure. The interaction enthalpy data were combined with data from the ligands solvation free energies or solvation enthalpies together with estimative data of the ligands entropic losses associated to the interaction with the enzyme in order to propose empirical equations for prediction of activities data through regressive fit by multiple correlation with available activity data. For the T. californica AChE, it was possible to develop three equations with good correlations for the three classes of compounds evaluated, which could be successfully applied for the prediction of inhibition data from calculated energy descriptors. Based on the analysis of the obtained structures for the mesoionic compounds and the corresponding empirical equation, we proposed the structures of xix two prototypes and determined their predicted activities. Both molecules were predicted as more active AChE inhibitors when compared to the compounds from which the new compounds were designed. For the Ae. aegypti AChE, it was possible to find an equation for the calculation of β-carbolines activities, which presented a good correlation with the experimental data. It was also proposed a prototype for the β-carbolines, based on the conformational restriction concept. Its AChE inhibition activity was calculated and the molecule was predicted as more active the compound from which the new compounds was designed.