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.

中文翻译：

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FFAR1调节剂立体选择性的机理研究

游离脂肪酸受体 1 (FFAR1) 是治疗 2 型糖尿病 (T2D) 的潜在治疗靶点。已经证实，靶向 FFAR1 的激动剂可以达到 T2D 的初始治疗终点，而差向异构体激动剂 ( R , S ) AM-8596 可以不同地激活 FFAR1，一种作为部分激动剂，另一种作为完全激动剂。到目前为止，FFAR1 激动剂的立体选择性的起源仍然难以捉摸。在这项工作中，我们使用分子模拟方法来阐明 FFAR1 激动剂 ( R )-AM-8596 和 ( S )-AM-8596 的立体选择性机制。我们发现完全激动剂（R)-AM-8596 破坏受体结合口袋周围的残基相互作用网络，促进 G 蛋白结合位点的开放，从而导致 FFAR1 的完全激活。相反，部分激动剂 ( S )-AM-8596 与 FFAR1 形成稳定的静电相互作用，从而稳定残基网络并阻碍受体的构象转变。因此，我们的工作阐明了 FFAR1 激动剂的选择性和潜在的分子激活机制。