Friedrich Nils-Ole, Simsir Méliné, Kirchmair Johannes
Department of Informatics, Center for Bioinformatics, Universität Hamburg, Hamburg, Germany.
Molécules Thérapeutiques In Silico, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
Front Chem. 2018 Mar 27;6:68. doi: 10.3389/fchem.2018.00068. eCollection 2018.
Knowledge of the bioactive conformations of small molecules or the ability to predict them with theoretical methods is of key importance to the design of bioactive compounds such as drugs, agrochemicals, and cosmetics. Using an elaborate cheminformatics pipeline, which also evaluates the support of individual atom coordinates by the measured electron density, we compiled a complete set ("Sperrylite Dataset") of high-quality structures of protein-bound ligand conformations from the PDB. The Sperrylite Dataset consists of a total of 10,936 high-quality structures of 4,548 unique ligands. Based on this dataset, we assessed the variability of the bioactive conformations of 91 small molecules-each represented by a minimum of ten structures-and found it to be largely independent of the number of rotatable bonds. Sixty-nine molecules had at least two distinct conformations (defined by an RMSD greater than 1 Å). For a representative subset of 17 approved drugs and cofactors we observed a clear trend for the formation of few clusters of highly similar conformers. Even for proteins that share a very low sequence identity, ligands were regularly found to adopt similar conformations. For cofactors, a clear trend for extended conformations was measured, although in few cases also coiled conformers were observed. The Sperrylite Dataset is available for download from http://www.zbh.uni-hamburg.de/sperrylite_dataset.
了解小分子的生物活性构象或用理论方法预测它们的能力对于设计生物活性化合物（如药物、农用化学品和化妆品）至关重要。我们使用了一个精心设计的化学信息学流程，该流程还通过测量的电子密度评估单个原子坐标的支持情况，从蛋白质数据银行（PDB）中汇编了一套完整的（“锌方解石数据集”）与蛋白质结合的配体构象的高质量结构。锌方解石数据集总共包含4548种独特配体的10936个高质量结构。基于这个数据集，我们评估了91个小分子（每个小分子至少由十个结构表示）的生物活性构象的变异性，发现其在很大程度上与可旋转键的数量无关。69个分子至少有两种不同的构象（由均方根偏差（RMSD）大于1 Å定义）。对于17种已批准药物和辅助因子的代表性子集，我们观察到形成高度相似构象的少数簇的明显趋势。即使对于序列同一性非常低的蛋白质，也经常发现配体采用相似的构象。对于辅助因子，测量到明显的伸展构象趋势，尽管在少数情况下也观察到卷曲构象。锌方解石数据集可从http://www.zbh.uni-hamburg.de/sperrylite_dataset下载。
