No abstract

Glycogen synthase kinase-3 beta (GSK-3β) is an enzyme pertinently linked to neurodegenerative diseases since it is associated with the regulation of key neuropathological features in the central nervous system. Among the different kinds of inhibitors of this kinase, the allosteric ones stand out due to their selective and subtle modulation, lowering the chance of producing side effects. The mechanism of GSK-3β allosteric modulators may be considered still vague in terms of elucidating a well-defined binding pocket and a bioactive pose for them. In this context, we propose to reinvestigate and reinforce such knowledge by the application of an extensive set of in silico methodologies, such as cavity detection, ligand 3D shape analysis and docking (with robust validation of corresponding protocols), and molecular dynamics. The results here obtained were consensually consistent in furnishing new structural data, in particular by providing a solid bioactive pose of one of the most representative GSK-3β allosteric modulators. We further applied this to the prospect for new compounds by ligand-based virtual screening and analyzed the potential of the two obtained virtual hits by quantum chemical calculations. All potential hits achieved will be subsequently tested by in vitro assays in order to validate our approaches as well as to unveil novel chemical entities as GSK-3β allosteric modulators.

Introduction: Neurodegenerative diseases (NDDs) are progressive, directly affecting the central nervous system (CNS), the most common and recurrent are Alzheimer's disease (AD) and Parkinson's disease (PD). One factor frequently mentioned in the etiology of NDDs is the generation of free radicals and oxidative stress, producing cellular damages. Studies have shown that the consumption of foods rich in polyphenols, especially those of the flavonoid class, has been related to the low risk in the development of several diseases. Due to the antioxidant properties present in the food, a fruit that has been gaining prominence among these foods is the Euterpe oleracea Mart. (açaí), because it presents in its composition significant amounts of a subclass of the flavonoids, the anthocyanins. Methods: In the case review, the authors receive a basic background on the most common NDDs, oxidative stress and antioxidants. In addition, revisiting the various studies related to NDDs, including flavonoids and consumption of açaí. Results: Detailed analysis of the recently reported case studies reveal that dietary consumption of flavonoid-rich foods, such as açaí fruits, suggests the efficacy to attenuate neurodegeneration and prevent or reverse the age-dependent deterioration of cognitive function. Conclusion: This systematic review points out that flavonoids presenting in açaí have the potential for the treatment of diseases such as PD and AD and are candidates for drugs in future clinical research. However, there is a need for in vitro and in vivo studies with polyphenol that prove and ratify the therapeutic potential of this fruit for several NDDs.

Background: Euterpe oleracea Martius, popularly known as açaí, is a fruit rich in α-tocopherols, fibers, lipids, mineral ions and polyphenols. It is believed that the high content of polyphenols, specially flavonoids, provides several health-promoting effects to the açaí fruit, including anti-inflammatory, immunomodulatory, antinociceptive and antioxidant properties. Most of flavonoids are antioxidant molecules from vegetable origin that act as a trap for free radicals, reacting and neutralizing them, thus offering perspectives in preventing oxidative damage. Objective: In this study we aim to perform an in silico evaluation of flavonoids present in the pulp and in the oil of Euterpe oleracea Martius, and their potential to represent antioxidant agents. Methods: First, we selected 16 flavonoid molecules present in Euterpe oleracea Martius pulp and oil, and then their physicochemical properties were analysed with respect to the Lipinski’s rule of five. Moreover, we evaluated their pharmacokinetic properties using the QikProp module of the Schrödinger software and their toxicity profile using the DEREK software. Docking simulations in the GOLD 4.1 software and calculation of the pharmacophore hypothesis of molecules were also performed. Results: Flavonoids present in the açaí pulp, catechin, epicatechin, luteolin, chrisoeriol, taxifolin, apigenin, dihydrokaempferol, isovitexin and vitexin presented good oral bioavailability. Regarding pharmacokinetic properties, the compounds catechin, epicatechin, isovitexin, luteolin, chrisoeriol, taxifolin and isorhamnetina rutinoside presented the best results and high human oral absorption. In the prediction of toxicological properties, compounds isorhamnetin rutinoside and rutin presented alert concerning mutagenicity for hydroxynaphthalene or derivate, and in docking simulations all the compounds presented key interactions with the corresponding targets tested. Conclusion: The flavonoids catechin, chrysoeriol and taxifolin presented overall best results, allowing such computational results to serve as a theoretical basis for future studies of developing drug candidates for biological tests in vitro and in vivo, which can contribute to the treatment of neurodegenerative diseases.

Among neurodegenerative disorders, Alzheimer's disease (AD) is the most common type of dementia, and there is an urgent need to discover new and efficacious forms of treatment for it. Pathological patterns of AD include cholinergic dysfunction, increased β‐amyloid (Aβ) peptide concentration, the appearance of neurofibrillary tangles, among others, all of which are strongly associated with specific biological targets. Interactions observed between these targets and potential drug candidates in AD most often occur by competitive mechanisms driven by orthosteric ligands that sometimes result in the production of side effects. In this context, the allosteric mechanism represents a key strategy; this can be regarded as the selective modulation of such targets by allosteric modulators in an advantageous manner, as this may decrease the likelihood of side effects. The purpose of this review is to present an overview of compounds that act as allosteric modulators of the main biological targets related to AD.