AMPA Receptor Noncompetitive Inhibitors Occupy a Promiscuous Binding Site
AMPA Receptor Noncompetitive Inhibitors Occupy a Promiscuous Binding Site
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DOI：
10.1021/acschemneuro.9b00344
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发表时间：
2019-11-01
影响因子：
5
通讯作者：
Kurnikova, Maria G.
中科院分区：
文献类型：
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作者：
Narangoda, Chamali;Sakipov, Serzhan N.;Kurnikova, Maria G.
AMPA受体的非竞争性抑制剂近年来作为抗癫痫药物引起了人们的兴趣。然而，由于缺乏对蛋白质-抑制剂相互作用机制的详细了解，它们的发展受到阻碍。最近，AMPA受体复合物与结构不同，非竞争性的小分子抑制剂pyridone perampanel (PMP), GYKI 53655 （GYKI）和CP 465022 （CP）的结构被解析，表明这三者具有共同的结合位点。然而，由于配体的低分辨率，它们的确切结合模式和蛋白质与配体的相互作用仍然不明确，也不够详细。我们对x射线分辨和对接的AMPA受体复合物进行了分子动力学（MD）模拟，包括热力学积分（TI）来计算配体结合常数，以详细研究抑制剂的结合模式并确定关键的蛋白质-配体相互作用机制。我们的分析和模拟表明，受体跨膜结构域界面的配体结合袋也具有在多药耐药蛋白的结合袋中发现的特征。抑制剂通过形成多个弱接触与这种混杂的口袋结合，而大而灵活的口袋经过调整以适应不同方向的结构不同的配体。TI能够确定GYKI的特定更有利的结合模式，而具有对称环结构的PMP产生了几个可比较的姿势，表明它可以在几个方向上结合。
Noncompetitive inhibitors of AMPA receptors have attracted interest in recent years as antiepileptic drugs. However, their development is hindered by a lack of detailed understanding of the protein-inhibitor interaction mechanisms. Recently, structures of AMPA receptor complexes with the structurally dissimilar, noncompetitive, small-molecule inhibitors pyridone perampanel (PMP), GYKI 53655 (GYKI), and CP 465022 (CP) were resolved, revealing that all three share a common binding site. However, due to the low resolution of the ligands, their exact binding modes and protein-ligand interactions remain ambiguous and insufficiently detailed. We carried out molecular dynamics (MD) simulations on X-ray-resolved and docked AMPA receptor complexes, including thermodynamic integration (TI) to compute ligand binding constants, in order to investigate the inhibitor binding modes in detail and identify key protein-ligand interaction mechanisms. Our analysis and simulations show that the ligand binding pocket at the interface of the receptor's transmembrane domain exhibits features also found in the binding pockets of the multidrug-resistance proteins. The inhibitors bind to such promiscuous pockets by forming multiple weak contacts, while the large, flexible pocket undergoes adjustments to accommodate structurally different ligands in different orientations. TI was able to identify a specific more favorable binding mode for GYKI, while PMP, which has a symmetric ring structure, produced several comparable poses indicating that it may bind in several orientations.