Yoon Sukjoon, Smellie Andrew, Hartsough David, Filikov Anton
ArQule, Inc., Woburn, Massachusetts 01801, USA.
Proteins. 2005 May 15;59(3):434-43. doi: 10.1002/prot.20428.
At the stage of optimization of a chemical series the compounds are normally assayed for binding or inhibition on the target protein as well as on several proteins from a selectivity panel. These proteins are normally identified on the basis of sequence homology to the target protein. Experimental selectivity data are also taken into account if available. Cases when a nonhomologous protein has a significant affinity to the compound series are going to be missed if the selectivity panel is identified by homology. Experimental data is usually either unavailable or limited to a small fraction of proteins that should be considered. We have developed a computational method of identification of selectivity panel proteins. It is based on the evaluation of binding site similarity to the target protein using docking scores of target-selected molecular probes. These probes are obtained by docking a large library of drug-like compounds to the target protein followed by selecting a diverse subset from the best virtual binders. Docking scores of these probes to other proteins measure binding site similarity to the target. Because the method does not require prior knowledge of either affinities or structures of inhibitors for the target, it can be applied to any protein with known 3D structure. Validation of the method includes rediscovery of nonhomologous proteins that bind common ligands: estradiol, tamoxifen, and riboflavin. Given 3D structures, the method can effectively discriminate proteins with similar binding sites from random proteins independent of sequence homology.
在化学系列优化阶段，通常会对化合物进行检测，以确定其对目标蛋白以及来自选择性筛选组的几种蛋白的结合或抑制情况。这些蛋白通常是根据与目标蛋白的序列同源性来确定的。如有可用的实验选择性数据，也会予以考虑。如果通过同源性来确定选择性筛选组，那么当非同源蛋白对化合物系列具有显著亲和力时，这种情况将会被遗漏。实验数据通常要么不可用，要么仅限于应考虑的一小部分蛋白。我们开发了一种计算方法来识别选择性筛选组蛋白。它基于使用目标选择的分子探针的对接分数来评估与目标蛋白的结合位点相似性。这些探针是通过将一个大型类药物化合物库与目标蛋白对接，然后从最佳虚拟结合物中选择一个多样化的子集而获得的。这些探针与其他蛋白的对接分数衡量了与目标蛋白的结合位点相似性。由于该方法不需要事先了解目标蛋白抑制剂的亲和力或结构，因此它可以应用于任何具有已知三维结构的蛋白。该方法的验证包括重新发现结合常见配体（雌二醇、他莫昔芬和核黄素）的非同源蛋白。给定三维结构，该方法可以有效地将具有相似结合位点的蛋白与随机蛋白区分开来，而不受序列同源性的影响。
