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

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 36; no. 1; pp. 1650 - 1657
• Main Authors: Lukin, Alexey, Bakholdina, Anna, Chudinov, Mikhail, Onopchenko, Oleksandra, Zhuravel, Elena, Zozulya, Sergey, Gureev, Maxim, Krasavin, Mikhail
• Format: Journal Article
• Language: English
• Published: Taylor & Francis 01-01-2021; Taylor & Francis Group
• Subjects: Brief Report; docking score; free fatty acid receptor 1 agonist; g protein-coupled receptor; phospholipid cell membrane bilayer; Short Communication; strained ligand interactions with cell membrane
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2021.1955874

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.