SAR by kinetics for drug discovery in protein misfolding diseases.
Proc Natl Acad Sci U S A
; 115(41): 10245-10250, 2018 10 09.
Article
em En
| MEDLINE
| ID: mdl-30257937
ABSTRACT
To develop effective therapeutic strategies for protein misfolding diseases, a promising route is to identify compounds that inhibit the formation of protein oligomers. To achieve this goal, we report a structure-activity relationship (SAR) approach based on chemical kinetics to estimate quantitatively how small molecules modify the reactive flux toward oligomers. We use this estimate to derive chemical rules in the case of the amyloid beta peptide (Aß), which we then exploit to optimize starting compounds to curtail Aß oligomer formation. We demonstrate this approach by converting an inactive rhodanine compound into an effective inhibitor of Aß oligomer formation by generating chemical derivatives in a systematic manner. These results provide an initial demonstration of the potential of drug discovery strategies based on targeting directly the production of protein oligomers.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
/
Relação Estrutura-Atividade
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Peptídeos beta-Amiloides
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Descoberta de Drogas
/
Doença de Alzheimer
Limite:
Humans
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Reino Unido