Ensemble-Based Steered Molecular Dynamics Predicts Relative Residence Time of A2A Receptor Binders.
Ensemble-Based Steered Molecular Dynamics Predicts Relative Residence Time of A2A Receptor Binders.
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DOI：
10.1021/acs.jctc.8b01270
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发表时间：
2019-03
影响因子：
5.5
通讯作者：
Andrew Potterton;Fouad S. Husseini;M. Southey;M. Bodkin;Alexander Heifetz;P. Coveney;A. Townsend-Nicholson
中科院分区：
文献类型：
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作者：
Andrew Potterton;Fouad S. Husseini;M. Southey;M. Bodkin;Alexander Heifetz;P. Coveney;A. Townsend-Nicholson
药物靶点停留时间，即小分子与其受体靶点结合的时间长度，已日益成为药物发现计划优化的关键特性。然而，事实证明，它的计算机预测很困难。在这里，我们描述了一种方法，使用基于原子系综的转向分子动力学 (SMD)，在适合药物发现的时间尺度内观察配体与其目标 G 蛋白偶联受体的解离。这些解离模拟准确、精确且可重复地识别配体-残基相互作用，并量化蛋白质和水的配体能量值的变化。该方法已应用于 A2A 腺苷受体的 17 个配体，所有配体均已发表实验动力学结合数据。实验已知配体解离时与配体相互作用的残基对结合亲和力和停留时间有影响。计算计算出的水-配体相互作用能的变化与实验确定的停留时间之间存在良好的相关性（R2 = 0.79）。我们的结果表明，基于集合的 SMD 是一种快速、新颖且准确的半经验方法，用于确定药物靶点相对停留时间。
Drug-target residence time, the length of time for which a small molecule stays bound to its receptor target, has increasingly become a key property for optimization in drug discovery programs. However, its in silico prediction has proven difficult. Here we describe a method, using atomistic ensemble-based steered molecular dynamics (SMD), to observe the dissociation of ligands from their target G protein-coupled receptor in a time scale suitable for drug discovery. These dissociation simulations accurately, precisely, and reproducibly identify ligand-residue interactions and quantify the change in ligand energy values for both protein and water. The method has been applied to 17 ligands of the A2A adenosine receptor, all with published experimental kinetic binding data. The residues that interact with the ligand as it dissociates are known experimentally to have an effect on binding affinities and residence times. There is a good correlation ( R2 = 0.79) between the computationally calculated change in water-ligand interaction energy and experimentally determined residence time. Our results indicate that ensemble-based SMD is a rapid, novel, and accurate semi-empirical method for the determination of drug-target relative residence time.