RIKEN Innovation Center, Nakamura Laboratory, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Molecules. 2018 Feb 15;23(2):425. doi: 10.3390/molecules23020425.
The octanol-water partition coefficient (log) is an important index for measuring solubility, membrane permeability, and bioavailability in the drug discovery field. In this paper, the log values of 58 compounds were predicted by alchemical free energy calculation using molecular dynamics simulation. In free energy calculations, the atomic charges of the compounds are always fixed. However, they must be recalculated for each solvent. Therefore, three different sets of atomic charges were tested using quantum chemical calculations, taking into account vacuum, octanol, and water environments. The calculated atomic charges in the different environments do not necessarily influence the correlation between calculated and experimentally measured ∆ values. The largest correlation coefficient values of the solvation free energy in water and octanol were 0.93 and 0.90, respectively. On the other hand, the correlation coefficient of log values calculated from free energies, the largest of which was 0.92, was sensitive to the combination of the solvation free energies calculated from the calculated atomic charges. These results reveal that the solvent assumed in the atomic charge calculation is an important factor determining the accuracy of predicted log values.
辛醇-水分配系数（log）是衡量药物发现领域溶解度、膜通透性和生物利用度的重要指标。在本文中，通过分子动力学模拟的量子力学自由能计算预测了 58 种化合物的 log 值。在自由能计算中，化合物的原子电荷通常是固定的。然而，它们必须针对每种溶剂重新计算。因此，本文使用量子化学计算测试了三组不同的原子电荷，考虑了真空、辛醇和水环境。不同环境下计算出的原子电荷不一定会影响计算和实验测量的 ∆ 值之间的相关性。在水中和辛醇中，溶剂化自由能的最大相关系数值分别为 0.93 和 0.90。另一方面，从自由能计算得出的 log 值的相关系数最大为 0.92，对从计算原子电荷计算得出的溶剂化自由能的组合较为敏感。这些结果表明，在原子电荷计算中假设的溶剂是决定预测 log 值准确性的重要因素。
