Structure-based design of free fatty acid receptor 1 agonists bearing non-biphenyl scaffold.
Bioorg Chem
; 80: 296-302, 2018 10.
Article
em En
| MEDLINE
| ID: mdl-29980115
ABSTRACT
The free fatty acid receptor 1 (FFA1) enhances the glucose-stimulated insulin secretion without the risk of hypoglycemia. However, most of FFA1 agonists have a common biphenyl moiety, leading to a relative deprivation in structure types. Herein, we describe the exploration of non-biphenyl scaffold based on the co-crystal structure of FFA1 to increase additional interactions with the lateral residues, which led to the identification of lead compounds 3 and 9. In induced-fit docking study, compound 3 forms an edge-on interaction with Trp150 by slightly rotating the indole ring of Trp150, and compound 9 has additional hydrogen bond and δ-π interactions with Leu135, which demonstrated the feasibility of our design strategy. Moreover, lead compounds 3 and 9 revealed improved polar surface area compared to GW9508, and have considerable hypoglycemic effects in mice. This structure-based study might inspire us to design more promising FFA1 agonists by increasing additional interactions with the residues outside of binding pocket.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Desenho de Fármacos
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Receptores Acoplados a Proteínas G
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Hipoglicemiantes
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article