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

Michael Lückmann; Mette Trauelsen; Marie A Bentsen; Tinne A D Nissen; Joao Martins; Zohreh Fallah; Mads M Nygaard; Elena Papaleo; Kresten Lindorff-Larsen; Thue W Schwartz; Thomas M Frimurer

doi:10.1073/pnas.1811066116

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

Michael Lückmann, Mette Trauelsen, Marie A Bentsen, Tinne A D Nissen, Joao Martins, Zohreh Fallah, Mads M Nygaard, Elena Papaleo, Kresten Lindorff-Larsen, Thue W Schwartz, Thomas M Frimurer

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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 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.

Original language	English
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	116
Issue number	14
Pages (from-to)	7123-7128
ISSN	0027-8424
DOIs	https://doi.org/10.1073/pnas.1811066116
Publication status	Published - 2 Apr 2019

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Lückmann, M., Trauelsen, M., Bentsen, M. A., Nissen, T. A. D., Martins, J., Fallah, Z., Nygaard, M. M., Papaleo, E., Lindorff-Larsen, K., Schwartz, T. W., & Frimurer, T. M. (2019). Molecular dynamics-guided discovery of an ago-allosteric modulator for GPR40/FFAR1. Proceedings of the National Academy of Sciences of the United States of America, 116(14), 7123-7128. https://doi.org/10.1073/pnas.1811066116

Lückmann, M , Trauelsen, M , Bentsen, MA, Nissen, TAD, Martins, J, Fallah, Z, Nygaard, MM , Papaleo, E , Lindorff-Larsen, K , Schwartz, TW & Frimurer, TM 2019, 'Molecular dynamics-guided discovery of an ago-allosteric modulator for GPR40/FFAR1', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 14, pp. 7123-7128. https://doi.org/10.1073/pnas.1811066116

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title = "Molecular dynamics-guided discovery of an ago-allosteric modulator for GPR40/FFAR1",

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 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.",

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T1 - Molecular dynamics-guided discovery of an ago-allosteric modulator for GPR40/FFAR1

AU - Lückmann, Michael

AU - Trauelsen, Mette

AU - Bentsen, Marie A

AU - Nissen, Tinne A D

AU - Martins, Joao

AU - Fallah, Zohreh

AU - Nygaard, Mads M

AU - Papaleo, Elena

AU - Lindorff-Larsen, Kresten

AU - Schwartz, Thue W

AU - Frimurer, Thomas M

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N2 - 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.

AB - 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.

U2 - 10.1073/pnas.1811066116

DO - 10.1073/pnas.1811066116

M3 - Journal article

C2 - 30872479

SN - 0027-8424

VL - 116

SP - 7123

EP - 7128

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 14

ER -

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

Abstract

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