Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Endenicher Allee 19c, D-53115 Bonn, Germany.
Int J Mol Sci. 2020 May 27;21(11):3782. doi: 10.3390/ijms21113782.
(1) Background: Compounds with multitarget activity are of interest in basic research to explore molecular foundations of promiscuous binding and in drug discovery as agents eliciting polypharmacological effects. Our study has aimed to systematically identify compounds that form complexes with proteins from distinct classes and compare their bioactive conformations and molecular properties. (2) Methods: A large-scale computational investigation was carried out that combined the analysis of complex X-ray structures, ligand binding modes, compound activity data, and various molecular properties. (3) Results: A total of 515 ligands with multitarget activity were identified that included 70 organic compounds binding to proteins from different classes. These multiclass ligands (MCLs) were often flexible and surprisingly hydrophilic. Moreover, they displayed a wide spectrum of binding modes. In different target structure environments, binding shapes of MCLs were often similar, but also distinct. (4) Conclusions: Combined structural and activity data analysis identified compounds with activity against proteins with distinct structures and functions. MCLs were found to have greatly varying shape similarity when binding to different protein classes. Hence, there were no apparent canonical binding shapes indicating multitarget activity. Rather, conformational versatility characterized MCL binding.
(1) 背景：具有多靶标活性的化合物在基础研究中很有意义，可用于探索混杂结合的分子基础，在药物发现中也可作为引发多药效学作用的试剂。我们的研究旨在系统地鉴定与不同类别蛋白质形成复合物的化合物，并比较它们的生物活性构象和分子性质。(2) 方法：进行了大规模的计算研究，综合分析了复合物的 X 射线结构、配体结合模式、化合物活性数据和各种分子性质。(3) 结果：共鉴定出 515 种具有多靶标活性的配体，其中包括 70 种与不同类别蛋白质结合的有机化合物。这些多类配体（MCL）通常具有柔性和惊人的亲水性。此外，它们表现出广泛的结合模式。在不同的靶标结构环境中，MCL 的结合形状通常相似，但也有区别。(4) 结论：综合结构和活性数据分析鉴定出了对具有不同结构和功能的蛋白质具有活性的化合物。MCL 在与不同的蛋白质类别结合时，其形状相似性差异很大。因此，没有明显的典型结合形状表明具有多靶标活性。相反，构象的多样性是 MCL 结合的特征。
