Centre of Biomolecular Drug Research and Institute of Organic Chemistry, Leibniz Universität Hannover , Schneiderberg 38, D-30167 Hannover, Germany.
European Molecular Biology Laboratory , Meyerhofstr. 1, 69117 Heidelberg, Germany.
J Chem Inf Model. 2017 Jun 26;57(6):1488-1498. doi: 10.1021/acs.jcim.7b00246. Epub 2017 Jun 12.
Phosphodiesterases (PDE) hydrolyze both cyclic AMP and GMP (cAMP/cGMP) and are responsible for the regulation of their levels in a multitude of cellular functions. PDE10A is expressed in the brain and is a validated target for both schizophrenia and Huntington disease. Here, we address the identification of novel chemical scaffolds that may bind PDE10A via structure-based drug design. For this task, we use INPHARMA, an NMR-based method that measures protein-mediated interligand NOEs between pairs of weakly, competitively binding ligands. INPHARMA is applied to a combination of four chemically diverse PDE10A binding fragments, with the aim of merging their pharmacophoric features into a larger, tighter binding molecule. All four ligands bind the PDE10A cAMP binding domain with affinity in the micromolar range. The application of INPHARMA to identify the correct docking poses of these ligands is challenging due to the nature of the binding pocket and the high content of water-mediated intermolecular contacts. Nevertheless, ensemble docking in the presence of conserved water molecules generates docking poses that are in agreement with all sets of INPHARMA data. These poses are used to build a pharmacophore model with which we search the ZINC database.
磷酸二酯酶（PDE）可水解环 AMP 和 GMP（cAMP/cGMP），并负责调节多种细胞功能中它们的水平。PDE10A 在大脑中表达，是精神分裂症和亨廷顿病的有效靶点。在这里，我们通过基于结构的药物设计来确定可能与 PDE10A 结合的新型化学支架。为此，我们使用了基于 NMR 的方法 INPHARMA，该方法测量了两对弱、竞争性结合配体之间的蛋白介导的配体间 NOE。INPHARMA 应用于四种化学上不同的 PDE10A 结合片段的组合，目的是将它们的药效特征融合到一个更大、更紧密的结合分子中。所有四种配体均以微摩尔范围的亲和力与 PDE10A 的 cAMP 结合域结合。由于结合口袋的性质和水介导的分子间接触的含量高，INPHARMA 用于确定这些配体的正确对接构象具有挑战性。然而，在保守水分子存在下的整体对接产生与所有 INPHARMA 数据集一致的对接构象。这些构象用于构建一个药效团模型，我们使用该模型在 ZINC 数据库中进行搜索。
