Department of Chemistry, Pharmacology, and Biomedical Informatics, Center for Structural Biology, Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232-6600, USA.
Molecules. 2012 Aug 20;17(8):9971-89. doi: 10.3390/molecules17089971.
Stereochemistry is an important determinant of a molecule's biological activity. Stereoisomers can have different degrees of efficacy or even opposing effects when interacting with a target protein. Stereochemistry is a molecular property difficult to represent in 2D-QSAR as it is an inherently three-dimensional phenomenon. A major drawback of most proposed descriptors for 3D-QSAR that encode stereochemistry is that they require a heuristic for defining all stereocenters and rank-ordering its substituents. Here we propose a novel 3D-QSAR descriptor termed Enantioselective Molecular ASymmetry (EMAS) that is capable of distinguishing between enantiomers in the absence of such heuristics. The descriptor aims to measure the deviation from an overall symmetric shape of the molecule. A radial-distribution function (RDF) determines a signed volume of tetrahedrons of all triplets of atoms and the molecule center. The descriptor can be enriched with atom-centric properties such as partial charge. This descriptor showed good predictability when tested with a dataset of thirty-one steroids commonly used to benchmark stereochemistry descriptors (r² = 0.89, q² = 0.78). Additionally, EMAS improved enrichment of 4.38 versus 3.94 without EMAS in a simulated virtual high-throughput screening (vHTS) for inhibitors and substrates of cytochrome P450 (PUBCHEM AID891).
立体化学是分子生物活性的一个重要决定因素。立体异构体在与靶蛋白相互作用时，其效力可能有不同程度的差异，甚至可能产生相反的效果。立体化学是一种难以在 2D-QSAR 中表示的分子特性，因为它本质上是一种三维现象。大多数用于 3D-QSAR 的立体化学编码描述符的一个主要缺点是，它们需要启发式方法来定义所有的立体中心，并对其取代基进行排序。在这里，我们提出了一种新的 3D-QSAR 描述符，称为对映选择性分子不对称性（Enantioselective Molecular ASymmetry，简称 EMAS），它能够在没有这种启发式方法的情况下区分对映异构体。该描述符旨在测量分子整体对称形状的偏差。径向分布函数（Radial-Distribution Function，简称 RDF）确定了所有原子三重对和分子中心四面体的有符号体积。该描述符可以通过原子中心特性（如部分电荷）进行丰富。当用三十一种常用于立体化学描述符基准测试的类固醇数据集进行测试时，该描述符表现出良好的预测能力（r²=0.89，q²=0.78）。此外，在模拟虚拟高通量筛选（virtual high-throughput screening，简称 vHTS）中，EMAS 与没有 EMAS 的 CYP450（PUBCHEM AID891）抑制剂和底物相比，富集度提高了 4.38 倍，而没有 EMAS 的情况下提高了 3.94 倍。
