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“School of Nano-Sciences”

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Paper   IPM / Nano-Sciences / 15582
School of Nano Science
  Title:   Molecular dynamics-guided discovery of an ago-allosteric modulator for GPR40/FFAR1
  Author(s): 
1.  Michael Lückmann
2.  Mette Trauelsen
3.  Marie Bentsen
4.  Tinne Nissen
5.  Joao Martins
6.  Zohreh Fallah
7.  Mads Nygaard
8.  Elena Papaleo
9.  Kresten Lindorff-Larsen
10.  Thue Schwartz
11.  Thomas Frimurer
  Status:   Published
  Journal: PNAS
  No.:  13
  Vol.:  03
  Year:  2019
  Pages:   1811066116
  Publisher(s):   PNAS latest Articles
  Supported by:  IPM
  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 TMI, 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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