AI Article Synopsis

  • FFAR1/GPR40 is a receptor that binds to special fatty acids in specific locations between its parts.
  • When the fatty acid is removed, important parts of the receptor change shape, causing a nearby pocket to close.
  • Scientists found a new compound that can keep this pocket open, which could help in creating better medicines for diabetes by targeting this receptor in a new way.

Article Abstract

The long-chain fatty acid receptor FFAR1/GPR40 binds agonists in both an interhelical site between the extracellular segments of transmembrane helix (TM)-III and TM-IV and a lipid-exposed groove between the intracellular segments of these helices. Molecular dynamics simulations of FFAR1 with agonist removed demonstrated a major rearrangement of the polar and charged anchor point residues for the carboxylic acid moiety of the agonist in the interhelical site, which was associated with closure of a neighboring, solvent-exposed pocket between the extracellular poles of TM-I, TM-II, and TM-VII. A synthetic compound designed to bind in this pocket, and thereby prevent its closure, was identified through structure-based virtual screening and shown to function both as an agonist and as an allosteric modulator of receptor activation. This discovery of an allosteric agonist for a previously unexploited, dynamic pocket in FFAR1 demonstrates both the power of including molecular dynamics in the drug discovery process and that this specific, clinically proven, but difficult, antidiabetes target can be addressed by chemotypes different from existing ligands.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452680PMC
http://dx.doi.org/10.1073/pnas.1811066116DOI Listing

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