根据最近的毒蕈碱乙酰胆碱受体晶体结构的见解,正变构调节剂(PAMs)的结合模式是在假设PAMs应该结合到活性状态的细胞外表面的情况下预测的。一系列表征良好的腺苷PAMs(A1R,A2AR,A3R)和毒蕈碱乙酰胆碱(M1R,使用基于刚性和柔性受体CHARMM的分子对接对M5R)受体进行建模。腺苷受体的研究通过与特定激动剂放射性配体复合建模,研究了PAM活性的探针依赖性的分子基础。共有结合模式将几个化学系列的常见药效团特征映射到特异性结合相互作用。这些模型提供了PAM结合如何减缓激动剂放射性配体解离动力学的合理化。预测M1RPAMs结合在类似的M2RPAMLY2119620结合位点中。预测M5RNAM(ML-375)以独特的诱导配合受体构象结合在PAM(ML-380)结合位点中。©2017Wiley期刊,Inc.
Following insights from recent crystal structures of the muscarinic acetylcholine receptor, binding modes of Positive Allosteric Modulators (PAMs) were predicted under the assumption that PAMs should bind to the extracellular surface of the active state. A series of well-characterized PAMs for adenosine (A1 R, A2A R, A3 R) and muscarinic acetylcholine (M1 R, M5 R) receptors were modeled using both rigid and flexible receptor CHARMM-based molecular docking. Studies of adenosine receptors investigated the molecular basis of the probe-dependence of PAM activity by modeling in complex with specific agonist radioligands.
Consensus binding modes map common pharmacophore features of several chemical series to specific binding interactions. These models provide a rationalization of how PAM binding slows agonist radioligand dissociation kinetics. M1 R PAMs were predicted to bind in the analogous M2 R PAM LY2119620 binding site. The M5 R NAM (ML-375) was predicted to bind in the PAM (ML-380) binding site with a unique induced-fit receptor conformation. © 2017 Wiley Periodicals, Inc.