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.
J Chem Inf Model. 2012 Oct 22;52(10):2550-8. doi: 10.1021/ci3003304. Epub 2012 Sep 28.
Compounds with high-confidence target annotations and activity measurements in the original and current release of the ChEMBL database have been compared to better understand how the growth of compound activity data might influence the spectrum of ligand-target interactions and the degree of target promiscuity among active compounds. Compared to the original ChEMBL release, a significant increase in the proportion of target promiscuous compounds was observed in the current version. The presence of these compounds led to large-magnitude changes in compound activity-based target and target family relationships and to a reorganization of major target communities. Surprisingly, however, this strong trend toward increasing target promiscuity was largely caused by growth of compounds with exclusive IC(50) measurements. By contrast, compounds with available equilibrium constants, which were also added in large amounts, did not substantially alter compound-based target relationships and notably contribute to increasing target promiscuity. These findings suggest that apparent compound promiscuity is much dependent on experimental conditions under which activities are determined and that care should be taken when evaluating promiscuity and polypharmacology on the basis of assay-dependent activity measurements.
与原始版本的 ChEMBL 数据库相比，对在 ChEMBL 数据库的原始和当前版本中具有高置信度靶标注释和活性测量值的化合物进行了比较，以便更好地了解化合物活性数据的增长如何影响配体-靶标相互作用的范围和活性化合物中靶标的混杂程度。与原始 ChEMBL 版本相比，当前版本中观察到靶标混杂化合物的比例显著增加。这些化合物的存在导致基于化合物活性的靶标和靶标家族关系发生了大幅度变化，并导致主要靶标群落的重新组织。然而，令人惊讶的是，这种靶标混杂性增加的强烈趋势主要是由于具有独特 IC（50）测量值的化合物的增长所致。相比之下，具有可用平衡常数的化合物（也大量添加）并没有实质性地改变基于化合物的靶标关系，并且显著有助于增加靶标混杂性。这些发现表明，明显的化合物混杂性在很大程度上取决于测定活性的实验条件，并且在基于依赖于测定的活性测量值评估混杂性和多效性时应谨慎。
