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Molecular dynamics-guided discovery of an ago-allosteric modulator for GPR40/FFAR1

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journal contribution
posted on 30.03.2021, 12:54 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 Frimurer
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.

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 Sciences

Volume

116

Issue

14

Pages

7123 - 7128

Publisher

Proceedings of the National Academy of Sciences

Version

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

2019-043-14

Copyright date

2019

ISSN

0027-8424

eISSN

1091-6490

Language

en

Depositor

Dr Zohreh Fallah. Deposit date: 25 March 2021