Smith Richard D, Lu Jing, Carlson Heather A
Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, United States of America.
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, United States of America.
PLoS Comput Biol. 2017 Nov 10;13(11):e1005813. doi: 10.1371/journal.pcbi.1005813. eCollection 2017 Nov.
Previous studies have compared the physicochemical properties of allosteric compounds to non-allosteric compounds. Those studies have found that allosteric compounds tend to be smaller, more rigid, more hydrophobic, and more drug-like than non-allosteric compounds. However, previous studies have not properly corrected for the fact that some protein targets have much more data than other systems. This generates concern regarding the possible skew that can be introduced by the inherent bias in the available data. Hence, this study aims to determine how robust the previous findings are to the addition of newer data. This study utilizes the Allosteric Database (ASD v3.0) and ChEMBL v20 to systematically obtain large datasets of both allosteric and competitive ligands. This dataset contains 70,219 and 9,511 unique ligands for the allosteric and competitive sets, respectively. Physically relevant compound descriptors were computed to examine the differences in their chemical properties. Particular attention was given to removing redundancy in the data and normalizing across ligand diversity and varied protein targets. The resulting distributions only show that allosteric ligands tend to be more aromatic and rigid and do not confirm the increase in hydrophobicity or difference in drug-likeness. These results are robust across different normalization schemes.
以往的研究比较了变构化合物与非变构化合物的物理化学性质。这些研究发现，与非变构化合物相比，变构化合物往往更小、更刚性、更疏水且更具药物样性质。然而，以往的研究没有恰当地校正某些蛋白质靶点的数据比其他系统多得多这一事实。这引发了对可用数据中固有偏差可能导致的偏差的担忧。因此，本研究旨在确定先前的发现对添加更新数据的稳健程度。本研究利用变构数据库（ASD v3.0）和ChEMBL v20系统地获取变构配体和竞争性配体的大型数据集。该数据集分别包含变构集和竞争集的70219个和9511个独特配体。计算了与物理相关的化合物描述符，以检查它们化学性质的差异。特别注意去除数据中的冗余，并对配体多样性和不同蛋白质靶点进行归一化。所得分布仅表明变构配体往往更具芳香性和刚性，并未证实疏水性增加或药物样性质的差异。这些结果在不同的归一化方案中都是稳健的。
