Institute of General, Inorganic and Theoretical Chemistry, and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria.
J Chem Inf Model. 2020 Aug 24;60(8):3843-3853. doi: 10.1021/acs.jcim.0c00289. Epub 2020 Jul 20.
Reliable information on partition coefficients plays a key role in drug development, as solubility decisively affects bioavailability. In a physicochemical context, the partition coefficient of a solute between two different solvents can be described as a function of solvation free energies. Hence, substantial scientific efforts have been made toward accurate predictions of solvation free energies in various solvents. The grid inhomogeneous solvation theory (GIST) facilitates the calculation of solvation free energies. In this study, we introduce an extended version of the GIST algorithm, which enables the calculation for chloroform in addition to water. Furthermore, GIST allows localization of enthalpic and entropic contributions. We test our approach by calculating partition coefficients between water and chloroform for a set of eight small molecules. We report a Pearson correlation coefficient of 0.96 between experimentally determined and calculated partition coefficients. The capability to reliably predict partition coefficients between water and chloroform and the possibility to localize their contributions allow the optimization of a compound's partition coefficient. Therefore, we presume that this methodology will be of great benefit for the efficient development of pharmaceuticals.
关于分配系数的可靠信息在药物开发中起着关键作用，因为溶解度会显著影响生物利用度。在物理化学背景下，溶质在两种不同溶剂之间的分配系数可以描述为溶剂化自由能的函数。因此，人们做出了大量的科学努力来准确预测各种溶剂中的溶剂化自由能。非均匀网格溶剂化理论（GIST）有助于计算溶剂化自由能。在这项研究中，我们引入了 GIST 算法的扩展版本，该版本除了水之外还可以计算氯仿。此外，GIST 允许定位焓和熵的贡献。我们通过计算一组八个小分子在水和氯仿之间的分配系数来测试我们的方法。我们报告实验测定和计算分配系数之间的 Pearson 相关系数为 0.96。能够可靠地预测水和氯仿之间的分配系数，并能够定位它们的贡献，这使得化合物的分配系数可以得到优化。因此，我们推测这种方法将极大地有益于药物的高效开发。
