Addressing free fatty acid receptor 1 (FFAR1) activation using supervised molecular dynamics

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    The free fatty acid receptor 1 (FFAR1, formerly GPR40), is a potential G protein-coupled receptor (GPCR) target for the treatment of type 2 diabetes mellitus (T2DM), as it enhances glucose-dependent insulin secretion upon activation by endogenous long-chain free fatty acids. The presence of two allosterically communicating binding sites and the lack of the conserved GPCR structural motifs challenge the general knowledge of its activation mechanism. To date, four X-ray crystal structures are available for computer-aided drug design. In this study, we employed molecular dynamics (MD) and supervised molecular dynamics (SuMD) to deliver insights into the (un)binding mechanism of the agonist MK-8666, and the allosteric communications between the two experimentally determined FFAR1 binding sites. We found that FFAR1 extracellular loop 2 (ECL2) mediates the binding of the partial agonist MK-8666. Moreover, simulations showed that the agonists MK-8666 and AP8 are reciprocally stabilized and that AP8 influences MK-8666 unbinding from FFAR1.
    Original languageEnglish
    Pages (from-to)1181–1193
    Number of pages13
    JournalJournal of Computer-Aided Molecular Design
    Issue number11
    Early online date27 Aug 2020
    Publication statusPublished - Nov 2020

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    • FFAR1
    • G protein-coupled receptors (GPCRs)
    • GPR40
    • MD
    • Molecular dynamics
    • SuMD
    • Supervised molecular dynamics

    ASJC Scopus subject areas

    • Drug Discovery
    • Computer Science Applications
    • Physical and Theoretical Chemistry


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