School of Life Sciences, University of Essex, Wivenhoe Park, Colchester, CO4 3SQ, UK.
Centre for Sport, Exercise and Life Sciences, Coventry University, Alison Gingell Building, Coventry, CV1 5FB, UK.
J Comput Aided Mol Des. 2020 Nov;34(11):1181-1193. doi: 10.1007/s10822-020-00338-6. Epub 2020 Aug 27.
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.
游离脂肪酸受体 1（FFAR1，以前称为 GPR40）是治疗 2 型糖尿病（T2DM）的潜在 G 蛋白偶联受体（GPCR）靶点，因为它在被内源性长链游离脂肪酸激活时增强葡萄糖依赖性胰岛素分泌。两个变构通讯结合位点的存在以及缺乏保守的 GPCR 结构基序挑战了其激活机制的一般知识。迄今为止，已有四个 X 射线晶体结构可用于计算机辅助药物设计。在这项研究中，我们采用分子动力学（MD）和监督分子动力学（SuMD）来深入了解激动剂 MK-8666的（非）结合机制，以及两个实验确定的 FFAR1 结合位点之间的变构通讯。我们发现 FFAR1 细胞外环 2（ECL2）介导部分激动剂 MK-8666 的结合。此外，模拟表明激动剂 MK-8666 和 AP8 是相互稳定的，并且 AP8 影响 MK-8666 从 FFAR1 上的非结合。
