An Overview of Several Inhibitors for Alzheimer’s Disease: Characterization and Failure

Abstract

Amyloid beta (Aβ) oligomers are the most neurotoxic aggregates causing neuronal death and cognitive damage. A detailed elucidation of the aggregation pathways from oligomers to fibril formation is crucial to develop therapeutic strategies for Alzheimer’s disease (AD). Although experimental techniques rely on the measure of time- and space-average properties, they face severe difficulties in the investigation of Aβ peptide aggregation due to their intrinsically disorder character. Computer simulation is a tool that allows tracing the molecular motion of molecules; hence it complements Aβ experiments, as it allows to explore the binding mechanism between metal ions and Aβ oligomers close to the cellular membrane at the atomic resolution. In this context, integrated studies of experiments and computer simulations can assist in mapping the complete pathways of aggregation and toxicity of Aβ peptides. Aβ oligomers are disordered proteins, and due to a rapid exploration of their intrinsic conformational space in real-time, they are challenging therapeutic targets. Therefore, no good drug candidate could have been identified for clinical use. Our previous investigations identified two small molecules, M30 (2-Ohydroisoquinolin-2(1H)-ylethanamine) and Gabapentin, capable of Aβ binding and inhibiting molecular aggregation, synaptotoxicity, intracellular calcium signaling, cellular toxicity and memory losses induced by Aβ. Thus, we recommend these molecules as novel candidates to assist anti-AD drug discovery in the near future. This review discusses the most recent research investigations about the Aβ dynamics in water, close contact with cell membranes, and several therapeutic strategies to remove plaque formation.

Current Understanding of the Physiopathology, Diagnosis and Therapeutic Approach to Alzheimer’s Disease

“…A curative treatment of AD remains to be discovered. Currently, the therapeutic armory available focuses on symptom control in milder cases of the disease [ 94 , 95 , 96 ] ( Figure 4 ).…”

In Vivo Dynamic Movement of Polymerized Amyloid β in the Perivascular Space of the Cerebral Cortex in Mice

“…Until now, inhibition of Aβ production by γ-secretase inhibitors was unsuccessful [ 14 ], whereas therapies utilizing antibodies to Aβ have been only partially successful [ 15 ]. As oligomerization of Aβ is now regarded as the first step in AD development, enhanced wash-out of Aβ from the cerebral cortex through the perivascular space might reduce toxicity of the Aβ [ 16 ].…”

Identification of Catechins Binding Pockets in Monomeric Aβ42Through Ensemble Docking and MD Simulations

“…Finding aggregation inhibitors and direct targeting of monomeric IDPs via small molecules is a very active area of research and a wide variety of computational techniques have been applied, yet there are many inherent difficulties. 12–14, 27, 35–41 For example, most docking algorithms employ the flexible ligand and rigid receptor paradigm 42–44 but IDPs display high conformational heterogeneity, and ligand binding causes large structural changes in the IDP conformations. To circumvent this problem, heterogeneous conformational ensembles of IDPs have been used for docking studies.…”