Predictions of Ligand Selectivity from Absolute Binding Free Energy Calculations.
Predictions of Ligand Selectivity from Absolute Binding Free Energy Calculations.
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从绝对结合自由能计算中的配体选择性预测。
DOI：
10.1021/jacs.6b11467
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发表时间：
2017-01-18
影响因子：
15
通讯作者：
Biggin PC
中科院分区：
文献类型：
--
作者：
Aldeghi M;Heifetz A;Bodkin MJ;Knapp S;Biggin PC
结合选择性是开发安全药物的必要性，它是用于临床前靶标验证的化学探针的关键特性。工程选择性为新药的合理设计增添了相当大的复杂性，因为它涉及多种结合亲和力的优化。从计算上讲，结合选择性的预测是一个挑战，通常适用的方法论仍然不适用于计算和药物化学群落。基于炼金术途径的绝对结合自由能计算为亲和力预测提供了严格的框架，因此可以为问题提供一般方法。我们通过估计多个溴化域家族的三个溴结构域抑制剂的亲和力分布，并通过将结果与等温滴定热量法数据进行比较，评估了基于分子动力学的自由能计算的性能，以预测选择性。考虑了两个案例研究。在第一个中，计算了两个相似的配体的亲和力，并与实验返回了极好的一致性（平均无符号误差为0.81 kcal/mol，Pearson相关性为0.75）。在此测试案例中，我们还展示了如何通过自由能计算来估算配体的首选结合方向。在第二种情况下，计算了广谱抑制剂对22个溴结构域的亲和力，并返回了更适度的精度（平均无符号误差为1.76 kcal/mol，Pearson相关性为0.48）；但是，磺酰胺部分的重新训练改善了与实验的一致性。
Binding selectivity is a requirement for the development of a safe drug, and it is a critical property for chemical probes used in preclinical target validation. Engineering selectivity adds considerable complexity to the rational design of new drugs, as it involves the optimization of multiple binding affinities. Computationally, the prediction of binding selectivity is a challenge, and generally applicable methodologies are still not available to the computational and medicinal chemistry communities. Absolute binding free energy calculations based on alchemical pathways provide a rigorous framework for affinity predictions and could thus offer a general approach to the problem. We evaluated the performance of free energy calculations based on molecular dynamics for the prediction of selectivity by estimating the affinity profile of three bromodomain inhibitors across multiple bromodomain families, and by comparing the results to isothermal titration calorimetry data. Two case studies were considered. In the first one, the affinities of two similar ligands for seven bromodomains were calculated and returned excellent agreement with experiment (mean unsigned error of 0.81 kcal/mol and Pearson correlation of 0.75). In this test case, we also show how the preferred binding orientation of a ligand for different proteins can be estimated via free energy calculations. In the second case, the affinities of a broad-spectrum inhibitor for 22 bromodomains were calculated and returned a more modest accuracy (mean unsigned error of 1.76 kcal/mol and Pearson correlation of 0.48); however, the reparametrization of a sulfonamide moiety improved the agreement with experiment.