RESUMO
Targeting the early oligomers formed by the amyloid-ß (Aß) peptide of 40 and 42 amino acids is considered one promising therapeutic approach for Alzheimer's disease (AD). In vitro experiments and computer simulations are often used in synergy to reveal the modes of interactions of drugs. In this account, we present our contribution to understanding how small molecules bind to Aß40/Aß42 peptides, based either on extensive coarse-grained and all-atom simulations, or a variety of experimental techniques. We conclude by offering several perspectives on the future of this field to design more efficient drugs.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Simulação por Computador , Modelos Moleculares , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/metabolismo , Doença de Alzheimer/metabolismo , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Fármacos Neuroprotetores/química , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Ligação Proteica , Conformação Proteica , Espécies Reativas de Oxigênio/metabolismoRESUMO
The two hallmarks of Alzheimer's disease (AD) are the presence of neurofibrillary tangles (NFT) made of aggregates of the hyperphosphorylated tau protein and of amyloid plaques composed of amyloid-ß (Aß) peptides, primarily Aß1-40 and Aß1-42. Targeting the production, aggregation, and toxicity of Aß with small molecule drugs or antibodies is an active area of AD research due to the general acceptance of the amyloid cascade hypothesis, but thus far all drugs targeting Aß have failed. From a review of the recent literature and our own experience based on in vitro, in silico, and in vivo studies, we present some reasons to explain this repetitive failure.
