Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom.
J Chem Inf Model. 2011 Mar 28;51(3):624-34. doi: 10.1021/ci1003174. Epub 2011 Feb 28.
Ligand promiscuity, which is now recognized as an extremely common phenomenon, is a major underlying cause of drug toxicity. We have developed a new reverse virtual screening (VS) method called ReverseScreen3D, which can be used to predict the potential protein targets of a query compound of interest. The method uses a 2D fingerprint-based method to select a ligand template from each unique binding site of each protein within a target database. The target database contains only the structurally determined bioactive conformations of known ligands. The 2D comparison is followed by a 3D structural comparison to the selected query ligand using a geometric matching method, in order to prioritize each target binding site in the database. We have evaluated the performance of the ReverseScreen2D and 3D methods using a diverse set of small molecule protein inhibitors known to have multiple targets, and have shown that they are able to provide a highly significant enrichment of true targets in the database. Furthermore, we have shown that the 3D structural comparison improves early enrichment when compared with the 2D method alone, and that the 3D method performs well even in the absence of 2D similarity to the template ligands. By carrying out further experimental screening on the prioritized list of targets, it may be possible to determine the potential targets of a new compound or determine the off-targets of an existing drug. The ReverseScreen3D method has been incorporated into a Web server, which is freely available at http://www.modelling.leeds.ac.uk/ReverseScreen3D .
配体混杂性，现在被认为是一种极其普遍的现象，是药物毒性的主要潜在原因。我们开发了一种新的反向虚拟筛选（VS）方法，称为 ReverseScreen3D，可用于预测查询化合物的潜在蛋白质靶标。该方法使用基于 2D 指纹的方法从目标数据库中每个蛋白质的每个独特结合位点中选择配体模板。目标数据库仅包含已知配体的结构确定的生物活性构象。2D 比较后，使用几何匹配方法对所选查询配体进行 3D 结构比较，以优先考虑数据库中的每个靶标结合位点。我们使用一组已知具有多个靶标的小分子蛋白抑制剂评估了 ReverseScreen2D 和 3D 方法的性能，并表明它们能够提供数据库中真实靶标的高度显著富集。此外，我们表明，与仅使用 2D 方法相比，3D 结构比较可以提高早期富集，并且即使与模板配体没有 2D 相似性，3D 方法也能很好地发挥作用。通过对优先靶目标列表进行进一步的实验筛选，可能确定新化合物的潜在靶标或确定现有药物的脱靶。ReverseScreen3D 方法已被纳入 Web 服务器，可在 http://www.modelling.leeds.ac.uk/ReverseScreen3D 上免费获得。
