Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität , Dahlmannstr. 2, D-53113 Bonn, Germany.
Pharmaceutical Institute, Rheinische Friedrich-Wilhelms-Universität , An der Immenburg 4, D-53121 Bonn, Germany.
J Med Chem. 2018 Feb 8;61(3):1276-1284. doi: 10.1021/acs.jmedchem.7b01780. Epub 2018 Jan 24.
Pan assay interference compounds (PAINS) have become a paradigm for compound classes that might cause artifacts in biological assays. PAINS-defining substructures are typically contained in larger compounds. We have systematically examined X-ray structures of protein-ligand complexes for compounds containing PAINS motifs. In 2874 X-ray structures, 1107 unique ligands with PAINS substructures belonging to 70 different classes were identified. PAINS most frequently detected in crystallographic ligands included a number of prominent candidates such as quinones, catechols, or Mannich bases. However, on the basis of X-ray data, the presence of specific ligand-target interactions and reactivity under assay conditions were not mutually exclusive. In some instances, reactivity of ligands was likely responsible for complex formation. Different categories of PAINS-containing ligands were distinguished, which aided in the interpretation of specific interactions versus potential assay artifacts. Careful consideration of structural data adds another dimension to the analysis of interference compounds.
泛分析干扰化合物 (PAINS) 已经成为一类可能在生物分析中产生假象的化合物的范例。PAINS 定义的亚结构通常包含在较大的化合物中。我们系统地检查了含有 PAINS 基序的化合物的蛋白质-配体复合物的 X 射线结构。在 2874 个 X 射线结构中，鉴定出 70 个不同类别中含有 PAINS 亚结构的 1107 个独特配体。在晶体学配体中最常检测到的 PAINS 包括一些著名的候选物，如醌、儿茶酚或曼尼希碱。然而，根据 X 射线数据，特定配体-靶标相互作用的存在和在测定条件下的反应性并非相互排斥。在某些情况下，配体的反应性可能是复合物形成的原因。区分了不同类别的含有 PAINS 的配体，这有助于解释特定的相互作用与潜在的测定假象。对结构数据的仔细考虑为干扰化合物的分析增加了另一个维度。
