Kolb Peter, Kipouros Catherine Berset, Huang Danzhi, Caflisch Amedeo
Department of Biochemistry, University of Zurich, CH-8057 Zurich, Switzerland.
Proteins. 2008 Oct;73(1):11-8. doi: 10.1002/prot.22028.
High-throughput docking is a computational tool frequently used to discover small-molecule inhibitors of enzymes or receptors of known three-dimensional structure. Because of the large number of molecules in chemical libraries, automatic procedures to prune multimillion compound collections are useful for high-throughput docking and necessary for in vitro screening. Here, we propose an anchor-based library tailoring approach (termed ALTA) to focus a chemical library by docking and prioritizing molecular fragments according to their binding energy which includes continuum electrostatics solvation. In principle, ALTA does not require prior knowledge of known inhibitors, but receptor-based pharmacophore information (hydrogen bonds with the hinge region) is additionally used here to identify molecules with optimal anchor fragments for the ATP-binding site of the EphB4 receptor tyrosine kinase. The 21,418 molecules of the focused library (from an initial collection of about 730,000) are docked into EphB4 and ranked by force-field-based energy including electrostatic solvation. Among the 43 compounds tested in vitro, eight molecules originating from two different anchors show low-micromolar activity in a fluorescence-based enzymatic assay. Four of them are active in a cell-based assay and are potential anti-angiogenic compounds.
高通量对接是一种计算工具，常用于发现已知三维结构的酶或受体的小分子抑制剂。由于化学文库中的分子数量众多，用于筛选数百万化合物集合的自动化程序对于高通量对接很有用，并且对于体外筛选是必要的。在此，我们提出了一种基于锚定的文库定制方法（称为ALTA），通过根据包括连续静电溶剂化在内的结合能对接分子片段并对其进行优先级排序，从而聚焦化学文库。原则上，ALTA不需要已知抑制剂的先验知识，但此处额外使用基于受体的药效团信息（与铰链区的氢键）来识别具有用于EphB4受体酪氨酸激酶ATP结合位点的最佳锚定片段的分子。聚焦文库中的21,418个分子（来自约730,000个的初始集合）被对接至EphB4，并根据包括静电溶剂化在内的基于力场的能量进行排名。在体外测试的43种化合物中，源自两个不同锚定的8个分子在基于荧光的酶促测定中显示出低微摩尔活性。其中4个在基于细胞的测定中具有活性，并且是潜在的抗血管生成化合物。
