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

Silvia Atanasio; Giuseppe Deganutti; Christopher A. Reynolds

doi:10.1007/s10822-020-00338-6

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

Silvia Atanasio, Giuseppe Deganutti, Christopher A. Reynolds

University of Essex

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5 Citations (Scopus)

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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 language	English
Pages (from-to)	1181–1193
Number of pages	13
Journal	Journal of Computer-Aided Molecular Design
Volume	34
Issue number	11
Early online date	27 Aug 2020
DOIs	https://doi.org/10.1007/s10822-020-00338-6
Publication status	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1007/s10822-020-00338-6

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Cite this

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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.",

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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