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Molecular dynamics-guided discovery of an ago-allosteric modulator for GPR40/FFAR1
journal contribution
posted on 2021-03-30, 12:54 authored by Michael Lückmann, Mette Trauelsen, Marie A Bentsen, Tinne AD Nissen, Joao Martins, Zohreh FallahZohreh Fallah, Mads M Nygaard, Elena Papaleo, Kresten Lindorff-Larsen, Thue W Schwartz, Thomas M FrimurerThe 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.
Funding
Novo Nordisk Foundation Center for Basic Metabolic Research (NNF10CC1016515)
Novo Nordisk Foundation Center for Protein Research (NNF14CC0001)
Challenge Grant NNF14OC0013655 from the Novo Nordisk Foundation
Sapere Aude Starting grant from the Independent Research Fund Denmark (DFF)
History
School
- Aeronautical, Automotive, Chemical and Materials Engineering
Department
- Materials
Published in
Proceedings of the National Academy of SciencesVolume
116Issue
14Pages
7123 - 7128Publisher
Proceedings of the National Academy of SciencesVersion
- VoR (Version of Record)
Publisher statement
This is an Open Access Article. It is published by Proceedings of the National Academy of Sciences under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) licence. Full details of this licence are available at: https://creativecommons.org/licenses/by-nc-nd/4.0/Publication date
2019-03-14Copyright date
2019ISSN
0027-8424eISSN
1091-6490Publisher version
Language
- en