Title : Seeking for Alzheimer´s disease cure by exploring in silico new targets and compounds
Abstract:
Alzheimer’s disease (AD) is an illness manifested by a number of pathological and clinical features, which including amyloid beta (Aβ) peptide deposits, neurofibrillary tangles (NFTs), dystrophic neurites, cholinergic impairment and neuronal death. To date, three acetylcholinesterase inhibitors (AChEi) (donepezil, rivastigmine and galanthamine) have been approved by the US Food and Drugs Administration (FDA) for its treatment, but these drugs provide symptomatic treatment but do not alter of curse of disease. The dysfunction of the cholinergic system in memory processing and storage is the base of the commonly accepted cholinergic hypothesis. According with hypothesis, in AD there are a loss of cholinergic neurons and nicotinic acetylcholine receptors (AChRs), which correlated with cognitive decline observed in the AD patients. AChEi enhance cholinergic neurotransmission by inhibiting the acetylcholinesterase (AChE) enzyme, which is responsible of the breakdown of the neurotransmitter acetylcholine (ACh), and this way, prolongs the action of the neurotransmitter at the synaptic cleft. However, recently it has also been shown that another type of cholinesterase, known such as butyrylcholinesterase (BChE) act as a co-regulator of cholinergic neurotransmission by hydrolyzing ACh, with a mechanism similar to AChE, this due to the functional and structural similarity of these enzymes. In recent years, there is a growing interest in the search of multifunctional compounds, which may represent an important pharmacological advance in the fight against the disease. In this context, compound combinations by synergistic effect could interfering simultaneously at different levels of the neurotoxic pathways. AD does not occur only by failing the cholinergic system. Neurotic plaque, cerebrovascular amyloidosis, and neurofibrillary tangles (NFTs) are considered marker of AD. Additionally, Peroxisome proliferator activated receptor gamma (PPARG) agonists reduce amyloid and tau pathologies, inhibit neuroinflammation and improve memory impairment in mild-to-moderate AD patients. However, they present poor blood brain barrier permeability, reducing their bioavailability. Other possible target that has been considered very important in AD is glycogen synthase kinase 3 beta (GSK3B) which plays an important role in the process of tau protein activation through phosphorylation. Therefore, GSK-3B inhibition is a potential approach for the treatment of AD. In the plants, we can find compounds with anti-cholinesterase, antigenotoxic, antioxidant, anti-inflammatory activity. This fact has motived a screening of new metabolites from Amaryllidaceae in view of their pharmacological potential. In natural products, we might find a source important of different molecules with potential to inhibit these four targets: AChE, BuChE, PPARG and GSK3B. Among the newer approaches in this research field, in silico molecular docking has been successfully used to identify, design and predict novel inhibitors. It is widely used in the discovery and optimization of novel compounds with affinity to a target; it also allows relating biological activity with the chemical constituent, which might give valuable hints for the prediction of biological activity. In this context, the present study aimed to evaluate the AChE, BChE, PPARG and GSK-3B inhibitory activity by some alkaloids belonging to Amaryllidaceae family members by applying in silico molecular docking complemented by biological experiments, which evaluated cytotoxicity and neuroprotective activity of alkaloids.
