Institute of Biomedicine, University of Turku, Turku, Finland.
Department of Biological and Environmental Science, University of Jyvaskyla, Jyvaskyla, Finland.
Chem Biol Drug Des. 2019 Oct;94(4):1799-1812. doi: 10.1111/cbdd.13584. Epub 2019 Jul 19.
A novel virtual screening methodology called fragment- and negative image-based (F-NiB) screening is introduced and tested experimentally using phosphodiesterase 10A (PDE10A) as a case study. Potent PDE10A-specific small-molecule inhibitors are actively sought after for their antipsychotic and neuroprotective effects. The F-NiB combines features from both fragment-based drug discovery and negative image-based (NIB) screening methodologies to facilitate rational drug discovery. The selected structural parts of protein-bound ligand(s) are seamlessly combined with the negative image of the target's ligand-binding cavity. This cavity- and fragment-based hybrid model, namely its shape and electrostatics, is used directly in the rigid docking of ab initio generated ligand 3D conformers. In total, 14 compounds were acquired using the F-NiB methodology, 3D quantitative structure-activity relationship modeling, and pharmacophore modeling. Three of the small molecules inhibited PDE10A at ~27 to ~67 μM range in a radiometric assay. In a larger context, the study shows that the F-NiB provides a flexible way to incorporate small-molecule fragments into the drug discovery.
一种新的虚拟筛选方法，称为基于片段和负像（F-NiB）的筛选方法，被引入并通过以磷酸二酯酶 10A（PDE10A）作为案例研究进行了实验测试。具有强大的 PDE10A 特异性的小分子抑制剂因其抗精神病和神经保护作用而受到广泛关注。F-NiB 结合了基于片段的药物发现和基于负像（NIB）筛选方法的特点，以促进合理的药物发现。与蛋白质结合的配体的选定结构部分与靶标配体结合腔的负像无缝结合。这种基于腔和片段的混合模型，即其形状和静电特性，直接用于从头生成的配体 3D 构象的刚性对接。总共使用 F-NiB 方法、3D 定量构效关系建模和药效团建模获得了 14 种化合物。其中三种小分子在放射性测定中以约 27 至约 67 μM 的范围抑制 PDE10A。从更大的角度来看，该研究表明 F-NiB 为将小分子片段纳入药物发现提供了一种灵活的方法。
