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.
journal_name
J Comput Aided Mol Desjournal_title
Journal of computer-aided molecular designauthors
Atanasio S,Deganutti G,Reynolds CAdoi
10.1007/s10822-020-00338-6subject
Has Abstractpub_date
2020-11-01 00:00:00pages
1181-1193issue
11eissn
0920-654Xissn
1573-4951pii
10.1007/s10822-020-00338-6journal_volume
34pub_type
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