Institute of Molecular Modeling and Simulation, University of Natural Resources and Life Sciences, 1190 Vienna, Austria.
Department of Cell and Molecular Biology, Uppsala University, SE-75124 Uppsala, Sweden.
Int J Mol Sci. 2019 Jul 16;20(14):3499. doi: 10.3390/ijms20143499.
Adenosine receptors are a family of G protein-coupled receptors with increased attention as drug targets on different indications. We investigate the thermodynamics of ligand binding to the A adenosine receptor subtype, focusing on a recently reported series of diarylacetamidopyridine inhibitors via molecular dynamics simulations. With a combined approach of thermodynamic integration and one-step perturbation, we characterize the impact of the charge distribution in a central heteroaromatic ring on the binding affinity prediction. Standard charge distributions according to the GROMOS force field yield values in good agreement with the experimental data and previous free energy calculations. Subsequently, we examine the thermodynamics of inhibitor binding in terms of the energetic and entropic contributions. The highest entropy penalties are found for inhibitors with methoxy substituents in meta position of the aryl groups. This bulky group restricts rotation of aromatic rings attached to the pyrimidine core which leads to two distinct poses of the ligand. Our predictions support the previously proposed binding pose for the o-methoxy ligand, yielding in this case a very good correlation with the experimentally measured affinities with deviations below 4 kJ/mol.
腺苷受体是一类 G 蛋白偶联受体，由于在不同适应症上作为药物靶点的关注度增加而备受关注。我们通过分子动力学模拟研究了配体与 A 腺苷受体亚型结合的热力学，重点关注了最近报道的一系列二芳基乙酰胺吡啶抑制剂。通过热力学积分和一步扰动的组合方法，我们描述了中央杂芳环中电荷分布对结合亲和力预测的影响。根据 GROMOS 力场的标准电荷分布得到的值与实验数据和以前的自由能计算结果非常吻合。随后，我们根据能量和熵贡献来研究抑制剂结合的热力学。在芳基的间位具有甲氧基取代基的抑制剂的熵罚最高。该庞大的基团限制了与嘧啶核心相连的芳环的旋转，导致配体呈现出两种不同的构象。我们的预测支持了先前提出的邻甲氧基配体的结合构象，在这种情况下，与实验测量的亲和力具有非常好的相关性，偏差低于 4 kJ/mol。
