Abstract

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.

摘要

合成了一组在酰胺部分带有取代联苯的 1,3,4-噻二唑-2-甲酰胺，并测试了对游离脂肪酸受体 1 (FFA1) 的激动活性。观察到的活动趋势不可能仅仅基于 Glide SP 的对接能量分数来合理化。相反，当围绕 FFA1 重建磷脂细胞膜双层时，很明显非活性化合物与膜的接触显着紧张，而对于活性化合物，应变明显较低。这些发现证明使用改进的对接协议对 GPCR-配体相互作用进行建模是合理的，该协议使用受体的晶体结构和细胞膜的重建部分。