ArticleProceedings of the National Academy of Sciences of the United States of America2019
Molecular dynamics-guided discovery of an ago-allosteric modulator for GPR40/FFAR1.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
17 citing papers in PubMed, 45 citations in OpenAlex.
- SCO-267, a GPR40 Full Agonist, Stimulates Islet and Gut Hormone Secretion and Improves Glycemic Control in Humans.Diabetes · 2021Trial
- AlloPool is a deep learning framework that infers protein allostery from molecular dynamics simulations.PLoS biology · 2026Article
- Structure-based discovery of positive allosteric modulators of the AProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Influence of the Water Model on the Structure and Interactions of the GPR40 Protein with the Lipid Membrane and the Solvent: Rigid versus Flexible Water Models.Journal of chemical theory and computation · 2024Article
- Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode.Nature communications · 2024Review
- Toward physics-based precision medicine: Exploiting protein dynamics to design new therapeutics and interpret variants.Protein science : a publication of the Protein Society · 2024Review
- Current Trends and Changes in Use of Membrane Molecular Dynamics Simulations within Academia and the Pharmaceutical Industry.Membranes · 2023Review
- Optimization of First-in-Class Dual-Acting FFAR1/FFAR4 Allosteric Modulators with Novel Mode of Action.ACS medicinal chemistry letters · 2022Article
- Computational approach for binding prediction of SARS-CoV-2 with neutralizing antibodies.Computational and structural biotechnology journal · 2022Article
- Current Trends in GPCR Allostery.The Journal of membrane biology · 2021Article
- Targeting lipid GPCRs to treat type 2 diabetes mellitus - progress and challenges.Nature reviews. Endocrinology · 2021Review
- G protein-coupled receptors: structure- and function-based drug discovery.Signal transduction and targeted therapy · 2021Review
- Addressing free fatty acid receptor 1 (FFAR1) activation using supervised molecular dynamics.Journal of computer-aided molecular design · 2020Article
- Advances in Molecular Dynamics Simulations and Enhanced Sampling Methods for the Study of Protein Systems.International journal of molecular sciences · 2020Review
- A simple open source bioinformatic methodology for initial exploration of GPCR ligands' agonistic/antagonistic properties.Pharmacology research & perspectives · 2020Article
- Molecular Mechanism for Attractant Signaling to DHMA by E. coli Tsr.Biophysical journal · 2020Article
- Omega-3 Fatty Acids as Druggable Therapeutics for Neurodegenerative Disorders.CNS & neurological disorders drug targets · 2019Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.