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Structural basis for the agonist action at free fatty acid receptor 1 (FFA1R or GPR40)

Daniel Alencar Rodrigues1,2, Pedro de Sena Murteira Pinheiro1,3, Thayssa Tavares da Silva Cunha Ferreira1,3

  • 1Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.

Chemical Biology & Drug Design
|October 26, 2017
PubMed

Insights

G-protein-coupled receptor 40 (GPR40) agonists show promise for type 2 diabetes treatment. This review details structure-activity relationships and medicinal chemistry strategies for developing novel GPR40 ligands.

Area of Science:

  • Medicinal Chemistry
  • Endocrinology
  • Pharmacology

Background:

  • G-protein-coupled receptor 40 (GPR40) is a key target for type 2 diabetes due to its role in insulin secretion from pancreatic beta cells.
  • Glucose stimulation of insulin secretion is dependent on GPR40 activity, making it a significant focus for therapeutic development.

Purpose of the Study:

  • To review the structure-activity relationships (SAR) of GPR40 agonists.
  • To highlight medicinal chemistry strategies employed in developing GPR40 agonist structural classes.
  • To present a general model for designing novel GPR40 ligands.

Main Methods:

  • Literature review of GPR40 agonist research.
  • Analysis of SAR data for various GPR40 agonist scaffolds.
  • Identification of common pharmacophoric features, such as the carboxylic acid group.

Main Results:

  • GPR40 agonists often feature a carboxylic acid group crucial for polar interactions within the receptor binding site.
  • Diverse structural patterns have been explored, each with specific SAR profiles.
  • Medicinal chemistry efforts have yielded several promising GPR40 agonist candidates.

Conclusions:

  • Understanding SAR is critical for optimizing GPR40 agonists.
  • The identified medicinal chemistry strategies and design model can guide the development of new type 2 diabetes therapies.
  • Further research into GPR40 modulation holds potential for improved diabetes management.
Keywords:
FFA1RGPR40GPR40 agonistsdiabetesfree fatty acid receptor 1

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