Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica "Pietro Pratesi", Università degli Studi di Milano , Via L. Mangiagalli 25, 20133 Milan, Italy.
Institute of Research in Biomedicine (IRB) , Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
J Chem Inf Model. 2015 Dec 28;55(12):2528-39. doi: 10.1021/acs.jcim.5b00459. Epub 2015 Nov 20.
Increasing attention has recently been devoted to allosteric modulators, as they can provide inherent advantages over classic receptor agonists. In the field of nicotinic receptors (nAChRs), the main advantage is that allosteric modulators can trigger pharmacological responses, limiting receptor desensitization. Most of the known allosteric ligands are "positive allosteric modulators" (PAMs), which increase both sensitivity to receptor agonists and current amplitude. Intriguingly, some allosteric modulators are also able to activate the α7 receptor (α7-nAChR) even in the absence of orthosteric agonists. These compounds have been named "ago-allosteric modulators" and GAT107 has been studied in depth because of its unique mechanism of action. We here investigate by molecular dynamics simulations, metadynamics, and essential dynamics the activation mechanism of α7-nAChR, in the presence of different nicotinic modulators. We determine the free energy profiles associated with the closed-to-open motion of the loop C, and we highlight mechanistic differences observed in the presence of different modulators. In particular, we demonstrate that GAT107 triggers conformational motions and cross-talk similar to those observed when the α7-nACh receptor is in complex with both an agonist and an allosteric modulator.
最近，人们越来越关注变构调节剂，因为它们相对于经典的受体激动剂具有内在优势。在烟碱型乙酰胆碱受体 (nAChR) 领域，主要的优势是变构调节剂可以引发药理学反应，限制受体脱敏。大多数已知的变构配体都是“正变构调节剂”(PAMs)，它们既能提高受体激动剂的敏感性，又能提高电流幅度。有趣的是，一些变构调节剂即使没有正变构激动剂也能激活 α7 受体(α7-nAChR)。这些化合物被称为“前变构调节剂”，由于其独特的作用机制，GAT107 已被深入研究。我们在这里通过分子动力学模拟、元动力学和基本动力学研究了不同烟碱类调节剂存在时 α7-nAChR 的激活机制。我们确定了与环 C 闭合到开放运动相关的自由能曲线，并突出了在存在不同调节剂时观察到的机制差异。特别是，我们证明 GAT107 触发的构象运动和串扰与当 α7-nACh 受体与激动剂和变构调节剂复合物时观察到的相似。
