Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35032, Marburg, Germany.
Abteilung für NMR-basierte Strukturbiologie, Max Planck Institut für Biophysikalische Chemie, Am Faßberg 11, 37077, Göttingen, Germany.
Angew Chem Int Ed Engl. 2017 Feb 6;56(7):1908-1913. doi: 10.1002/anie.201609824. Epub 2017 Jan 18.
With the rising popularity of fragment-based approaches in drug development, more and more attention has to be devoted to the detection of false-positive screening results. In particular, the small size and low affinity of fragments drives screening techniques to their limit. The pursuit of a false-positive hit can cause significant loss of time and resources. Here, we present an instructive and intriguing investigation into the origin of misleading assay results for a fragment that emerged as the most potent binder for the aspartic protease endothiapepsin (EP) across multiple screening assays. This molecule shows its biological effect mainly after conversion into another entity through a reaction cascade that involves major rearrangements of its heterocyclic scaffold. The formed ligand binds EP through an induced-fit mechanism involving remarkable electrostatic interactions. Structural information in the initial screening proved to be crucial for the identification of this false-positive hit.
随着碎片法在药物研发中的日益普及，人们越来越需要关注筛选结果中的假阳性问题。特别是，由于片段分子较小、亲和力较低，这促使筛选技术达到了极限。追求假阳性命中可能会导致大量时间和资源的浪费。在这里，我们介绍了一项具有启发性和趣味性的研究，该研究针对在多种筛选实验中表现出与天冬氨酸蛋白酶内切酶（EP）结合能力最强的片段的误导性检测结果的来源。该分子在通过涉及其杂环支架的重大重排的反应级联转化为另一种实体后，才显示出其生物效应。形成的配体通过涉及显著静电相互作用的诱导契合机制与 EP 结合。最初筛选中的结构信息对于鉴定这种假阳性命中至关重要。
