Computer-Chemie-Centrum and Interdisciplinary Center for Molecular Materials, Friedrich-Alexander Universitat Erlangen-Nurnberg, Nagelsbachstrasse 52, Erlangen, Germany.
J Chem Inf Model. 2010 Mar 22;50(3):429-36. doi: 10.1021/ci900431f.
Log P(OW), the negative logarithm of the octanol-water partition coefficient, is omnipresent in computational drug design. Here, we present a surface-integral model for calculating log P(OW). The model is based on local properties calculated using AM1 semiempirical molecular orbital theory. These are the molecular electrostatic potential (MEP), local ionization energy (IE(L)), local electron affinity (EA(L)), local hardness (HARD), local polarizability (POL), and the local field normal to the surface (FN). We have developed a new scheme to calculate a local hydrophobicity based on binning the range of local surface properties instead of using polynomial expansions of the base terms. The model has been trained using approximately 9500 compounds available from the literature. It was validated on approximately 1350 compounds from the literature and an in-house validation set of 768 compounds from Boehringer-Ingelheim. The model performs similarly to or slightly better than the best commercially available models. We also introduce a model based purely on conformationally rigid compounds that performs well for flexible compounds if the Boltzmann weighted predictions for the different conformers are used. This is the first 3D QSPR model based on such a large databasis that is able to benefit from using conformational ensembles.
分配系数的对数值（Log P(OW)）在计算药物设计中无处不在。在此，我们提出了一种计算 Log P(OW)的表面积分模型。该模型基于使用 AM1 半经验分子轨道理论计算的局部性质。这些性质包括分子静电势（MEP）、局部电离能（IE(L)）、局部电子亲和力（EA(L)）、局部硬度（HARD）、局部极化率（POL）和表面法向局部场（FN）。我们开发了一种新的方案，通过对局部表面性质的范围进行分组，而不是使用基本项的多项式展开，来计算局部疏水性。该模型使用来自文献中的约 9500 种化合物进行了训练。它在文献中约 1350 种化合物和勃林格殷格翰公司的 768 种内部验证集化合物上进行了验证。该模型的性能与最好的商业可用模型相似或略好。我们还引入了一个仅基于构象刚性化合物的模型，如果使用不同构象的玻尔兹曼加权预测，则该模型对柔性化合物的性能也很好。这是第一个基于如此大规模数据库的 3D QSPR 模型，能够从构象集合中受益。
