Strained contacts with the cell membrane may influence ligand affinity to G protein coupled receptors: a case of free fatty acid receptor 1 agonists

Autor: Alexey Lukin, Anna Bakholdina, Mikhail Chudinov, Oleksandra Onopchenko, Elena Zhuravel, Sergey Zozulya, Maxim Gureev, Mikhail Krasavin
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 36, Iss 1, Pp 1650-1657 (2021)
Druh dokumentu: article
ISSN: 1475-6366
1475-6374
14756366
DOI: 10.1080/14756366.2021.1955874
Popis: A set of 1,3,4-thiadiazole-2-carboxamides bearing a substituted biphenyl in the amide portion was synthesised and tested for agonistic activity towards free fatty acid receptor 1 (FFA1). The observed activity trends were impossible to rationalised based solely on the docking energy scores of Glide SP. On the contrary, when the phospholipid cell membrane bilayer was reconstructed around FFA1, it became apparent that inactive compounds displayed significant strained contacts with the membrane while for active compounds the strain was noticeably lower. These findings justify using the improved docking protocol for modelling GPCR-ligand interactions which uses the crystal structure of the receptor and a reconstructed portion of a cell membrane.
Databáze: Directory of Open Access Journals
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