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Mechanistic Studies...
Mechanistic Studies on the Stereoselectivity of FFAR1 Modulators
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- Teng, Dan (author)
- KTH,Teoretisk kemi och biologi,Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
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Zhou, Y. (author)
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Tang, Y. (author)
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Liu, G. (author)
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- Tu, Yaoquan (author)
- KTH,Teoretisk kemi och biologi
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(creator_code:org_t)
- 2022-07-25
- 2022
- English.
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In: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 62:15, s. 3664-3675
- Related links:
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https://doi.org/10.1...
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https://urn.kb.se/re...
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Abstract
Subject headings
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- Free fatty acid receptor 1 (FFAR1) is a potential therapeutic target for the treatment of type 2 diabetes (T2D). It has been validated that agonists targeting FFAR1 can achieve the initial therapeutic endpoints of T2D, and the epimer agonists (R,S) AM-8596 can activate FFAR1 differently, with one acting as a partial agonist and the other as a full agonist. Up to now, the origin of the stereoselectivity of FFAR1 agonists remains elusive. In this work, we used molecular simulation methods to elucidate the mechanism of the stereoselectivity of the FFAR1 agonists (R)-AM-8596 and (S)-AM-8596. We found that the full agonist (R)-AM-8596 disrupts the residue interaction network around the receptor binding pocket and promotes the opening of the binding site for the G-protein, thereby resulting in the full activation of FFAR1. In contrast, the partial agonist (S)-AM-8596 forms stable electrostatic interactions with FFAR1, which stabilizes the residue network and hinders the conformational transition of the receptor. Our work thus clarifies the selectivity and underlying molecular activation mechanism of FFAR1 agonists.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
Keyword
- Chemical activation
- Fatty acids
- Acid receptors
- Epimers
- Free fatty acid
- Interaction networks
- Mechanistic studies
- Molecular simulations
- Receptor binding
- Receptor-1
- Therapeutic targets
- Type-2 diabetes
- Stereoselectivity
- FFAR1 protein
- human
- G protein coupled receptor
- binding site
- chemistry
- human
- non insulin dependent diabetes mellitus
- Binding Sites
- Diabetes Mellitus
- Type 2
- Humans
- Receptors
- G-Protein-Coupled
Publication and Content Type
- ref (subject category)
- art (subject category)
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