Structural Isosteres of Phosphate Groups in the Protein Data Bank

We developed a computational
workflow to mine the Protein Data
Bank for isosteric replacements that exist in different binding site
environments but have not necessarily been identified and exploited
in compound design. Taking phosphate groups as examples, the workflow
was used to construct 157 data sets, each composed of a reference
protein complexed with AMP, ADP, ATP, or pyrophosphate as well other
ligands. Phosphate binding sites appear to have a high hydration content
and large size, resulting in U-shaped bioactive conformations recurrently
found across unrelated protein families. A total of 16 413
replacements were extracted, filtered for a significant structural
overlap on phosphate groups, and sorted according to their SMILES
codes. In addition to the classical isosteres of phosphate, such as
carboxylate, sulfone, or sulfonamide, unexpected replacements that
do not conserve charge or polarity, such as aryl, aliphatic, or positively
charged groups, were found.

本研究开发了一套计算流程，用于从蛋白质数据库（Protein Data Bank，PDB）中挖掘存在于不同结合位点环境中，但未必已在化合物设计中得到鉴定与应用的等排替换体（isosteric replacements）。
本研究以磷酸基团为例，利用该流程构建了157个数据集，每个数据集均包含一个与一磷酸腺苷（AMP）、二磷酸腺苷（ADP）、三磷酸腺苷（ATP）或焦磷酸（pyrophosphate）及其他配体结合的参考蛋白质复合物。磷酸结合位点通常具有较高的水合程度与较大的空间体积，由此形成的U型生物活性构象在无亲缘关系的蛋白质家族中反复出现。
本研究共提取得到16413个替换体，经筛选以确保其在磷酸基团上存在显著的结构重叠，并依据简化分子线性输入规范（SMILES）代码进行排序。除羧酸根（carboxylate）、砜基（sulfone）与磺酰胺（sulfonamide）等经典的磷酸等排体外，本研究还发现了一些不保留电荷或极性的非典型替换体，例如芳基（aryl）、脂肪族基团（aliphatic）或带正电的基团。