We apply the hit-to-lead ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) and lead-optimization TIES (thermodynamic integration with enhanced sampling) methods to compute the binding free energies of a series of ligands at the A₁ and A_2A adenosine receptors, members of a subclass of the GPCR (G protein-coupled receptor) superfamily. Our predicted binding free energies, calculated using ESMACS, show a good correlation with previously reported experimental values of the ligands studied. Relative binding free energies, calculated using TIES, accurately predict experimentally determined values within a mean absolute error of approximately 1 kcal mol⁻¹. Our methodology may be applied widely within the GPCR superfamily and to other small molecule–receptor protein systems.

我们应用hit-to-lead ESMACS（使用连续溶剂近似的分子动力学增强采样）和lead-optimization TIES（增强采样的热力学集成）方法来计算A ₁和甲_2A腺苷受体中，GPCR（G蛋白偶联受体）的一个子类超家族的成员。我们使用 ESMACS 计算的预测结合自由能显示出与先前报告的配体实验值的良好相关性。使用 TIES 计算的相对结合自由能在大约 1 kcal mol ^-1的平均绝对误差内准确预测实验确定的值. 我们的方法可以广泛应用于 GPCR 超家族和其他小分子受体蛋白系统。