Information School, The University of Sheffield, Regent Court, 211 Portobello, Sheffield, S1 4DP, UK.
Chemical Innovation Centre, Discovery Sciences, IMED Biotech Unit, AstraZeneca, Alderley Park, UK.
ChemMedChem. 2018 Mar 20;13(6):607-613. doi: 10.1002/cmdc.201700679. Epub 2018 Feb 12.
Bioisosterism is an important concept in the lead optimisation phase of drug discovery where the aim is to make modifications to parts of a molecule in order to improve some properties while maintaining others. We present an analysis of bioisosteric fragments extracted from the ligands in an established data set consisting of 121 protein targets. A pairwise analysis is carried out of all ligands for a given target. The ligands are fragmented using the BRICS fragmentation scheme and a pair of fragments is deemed to be bioisosteric if they occupy a similar volume of the protein binding site. We consider two levels of generality, one which does not consider the number of attachment points in the fragments and a more restricted case in which both fragments are required to have the same number of attachments. We investigate the extent to which the bioisosteric pairs that are found are common across different target.
生物等排是药物发现中先导化合物优化阶段的一个重要概念，其目的是对分子的某些部分进行修饰，以改善某些性质而保持其他性质不变。我们分析了从一个由 121 个蛋白质靶标组成的已有数据集的配体中提取的生物等排片段。对给定靶标的所有配体进行成对分析。配体使用 BRICS 片段化方案进行片段化，如果一对片段占据蛋白质结合位点的相似体积，则它们被认为是生物等排的。我们考虑了两种通用性水平，一种不考虑片段的附着点数量，另一种更严格的情况是要求两个片段具有相同数量的附着点。我们研究了在不同靶标中发现的生物等排对的普遍程度。
