Design and development of new potential anti-Alzheimer's agents based on the inhibition of acetylcholinesterase and glycogen synthase kinase 3-beta and anti-aggregation of the amyloid beta-peptide

Abstract

Alzheimer's disease (AD), despite its high prevalence and impact, still has no cure, constituting currently drug therapies as the main hope for disease control. Thus, there is a continued need for the discovery and design of new drugs, in order to enrich the arsenal of substances available for pharmacotherapy, whether inhibitors of acetylcholinesterase (AChE), glycogen synthase kinase 3-beta (GSK-3beta) or any another key target in the development of the disease.In previous design (Proc. FAPESP 2009 / 11208-6), trials with the selected compounds and human AChE in solution indicated an inhibition of enzyme activity up to 35% of the tested compounds, and 10 compounds showed three percentage AChE inhibition in solution of over 30%. After these results, 10 new compounds were designed, purchased and tested with AChE, and with the beta-amiloid peptide. Such compounds showed strong AChE inhibition, at low concentrations, and they also inhibited the beta-amiloid agreggation, with more intentensity than Donepezil!In this same project, trials with GSK-3beta inhibitors and designed in our laboratory (based planning binders) have generated promising results in inhibition of enzyme activity and selectivity compared to other homologous and relevant kinase in Alzheimer's disease, Casein kinase 1 (CK-1), where one of the compounds showed 34.3% inhibition of the GSK-3beta, 10 mM concentration and high selectivity in relation to its counterpart CK-1.For this new project proposal, including the enzymes AChE (Part 1 of this project) and GSK-3beta (Part 2 of this project), the goal is to extend the computational initially planning done in previous work with GSK-3b, which was only based on pharmacophore of ligands, the planning also based on structure as well as optimize the prototypes already obtained in that work. For AChE, the design of new anti-Alzheimer agents include, among others, a stage of search for new inhibitors of aggregation of the amyloid-beta peptide, by similarity with the structures and probable conformation in common (the 'Principle of Analog Active' ) more potent inhibitors of the aggregation of the peptide described in the literature, numbering about 60 compounds coplanar rings.With the strategy to be used if dares to predict the bioactive conformations of molecules (with respect to the inhibition of aggregation of ²-amyloid peptide) without having any data available on the structure of the complex with the peptide aggregation inhibitors. Also for this class of compounds is particularly aimed at building models using the 3D-QSAR descriptors GRIND second generation chemically so as to explain the structure-activity relationship aggregation inhibitors. Finally, the designed compounds will be purchased, tested and subsequently optimized in silico with respect to its pharmacodynamic and pharmacokinetic properties for later purposes of synthetic modification, patenting, etc.Assays of acetylcholinesterase inhibition and aggregation of amyloid-beta peptide will be conducted in collaboration with Prof.a. Dr.a. Wanda Almeida Pereira, Institute of Chemistry, UNICAMP in Campinas. The permeation studies of the blood brain barrier and preclinical studies with inhibitors of the two enzymes are conducted in collaboration with Prof.a. Dr.a. Ana Martinez Gil, a researcher at the Consejo Superior de Investigaciones Científicas - CSIC, Madrid, Spain, which is a member of our newly approved "Novel Potential Anti-Alzheimer's Agents: from Design to Preclinical Studies" project (FAPESP Call CSIC-2013 Proc. FAPESP 2013 / 50788-3). Finally, this proposal should have extensive technical and methodological support CEPID inflammatory diseases (CRID) - Proc. FAPESP 2013 / 08216-2, of which I am one of the principal investigators (PI) to investigate the relationship between Alzheimer's disease and associated neuroinflammatory processes. (AU)