Pairwise‐based methods such as the free energy perturbation (FEP) method have been widely deployed to compute the binding free energy differences between two similar host–guest complexes. The calculated pairwise free energy difference is either directly adopted or transformed to absolute binding free energy for molecule rank ordering. We investigated, through both analytic derivations and simulations, how the selection of pairs in the experiment could impact the overall prediction precision. Our studies showed that (1) the estimated absolute binding free energy ( ΔG^ ) derived from calculated pairwise differences (ΔΔG) through weighted least squares fitting is more precise in prediction than the pairwise difference values when the number of pairs is more than the number of ligands and (2) prediction precision is influenced by both the total number of pairs and the specifically selected pairs, the latter being critically important when the number of calculated pairs is limited. Furthermore, we applied optimal experimental design in pair selection and found that the optimally selected pairs can outperform randomly selected pairs in prediction precision. In an illustrative example, we showed that, upon weighing ligand structure similarity into design optimization, the weighted optimal designs are more efficient than the literature reported designs. This work provides a new approach to assess retrospective pairwise‐based prediction results, and a method to design new prospective pairwise‐based experiments for molecular lead optimization. © 2019 Wiley Periodicals, Inc.

中文翻译：

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成对计算的优化设计：自由能扰动在最小化预测变异性方面的应用

基于成对的方法，例如自由能扰动（FEP）方法已被广泛用于计算两个相似的主客体复合物之间的结合自由能差异。计算出的成对自由能差要么直接采用，要么转化为分子等级排序的绝对结合自由能。我们通过分析推导和模拟研究了实验中对的选择如何影响整体预测精度。我们的研究表明，（1）当对数大于数量时，通过加权最小二乘拟合计算出的成对差异（ΔΔG）得出的估计绝对结合自由能（ΔG^）比成对差异值更准确地预测配体的数量和 (2) 预测精度受总对数和特定选择对的影响，当计算对的数量有限时，后者至关重要。此外，我们在配对选择中应用了最佳实验设计，发现最佳选择的配对在预测精度上优于随机选择的配对。在一个说明性示例中，我们表明，在将配体结构相似性权衡到设计优化中后，加权优化设计比文献报道的设计更有效。这项工作提供了一种评估回顾性成对预测结果的新方法，以及一种为分子先导优化设计新的前瞻性成对实验的方法。© 2019 威利期刊公司。