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

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2 Citations (Scopus)

Abstract

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
Volume34
Issue number11
Early online date27 Aug 2020
DOIs
Publication statusPublished - Nov 2020

Bibliographical note

The final publication is available at Springer via http://dx.doi.org/10.1007/s10822-020-00338-6

Copyright © and Moral Rights are retained by the author(s) and/ or other copyright owners. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This item cannot be reproduced or quoted extensively from without first obtaining permission in writing from the copyright holder(s). The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the copyright holders.

Keywords

  • 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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