Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
J Med Chem. 2020 Sep 10;63(17):8901-8916. doi: 10.1021/acs.jmedchem.9b02021. Epub 2020 Apr 24.
Pyrazine-based compounds are of great importance in medicinal chemistry. Due to their heteroaromatic nature, they uniquely combine properties of heteroatoms (polar interactions) with the properties of aromatic moieties (nonpolar interactions). This review summarizes results of a systematic analysis of RCSB PDB database focused on important binding interactions of pyrazine-based ligands cocrystallized in protein targets. The most frequent interaction of pyrazine was hydrogen bond to pyrazine nitrogen atom as an acceptor, followed by weak hydrogen bond with pyrazine hydrogen as donor. We also identified intramolecular hydrogen bonds within pyrazine ligands, π-interactions, coordination to metal ions, and few halogen bonds in chloropyrazines. In many cases the binding mode of the pyrazine fragment was complex, involving a combination of several interactions. We conclude that pyrazine as a molecular fragment should not be perceived as a simple aromatic isostere but rather as a readily interacting moiety of drug-like molecules with high potential for interactions to proteins.
吡嗪类化合物在药物化学中具有重要意义。由于其杂芳环性质，它们独特地结合了杂原子的性质（极性相互作用）和芳基部分的性质（非极性相互作用）。本综述总结了对 RCSB PDB 数据库的系统分析结果，该数据库专注于与蛋白质靶标共结晶的吡嗪类配体的重要结合相互作用。吡嗪最常见的相互作用是吡嗪氮原子作为受体的氢键，其次是吡嗪氢作为供体的弱氢键。我们还确定了吡嗪配体内部的分子内氢键、π-相互作用、与金属离子的配位以及氯代吡嗪中的几个卤键。在许多情况下，吡嗪片段的结合模式很复杂，涉及几种相互作用的组合。我们得出结论，吡嗪作为一个分子片段，不应被视为简单的芳香等排体，而应被视为具有与蛋白质相互作用的高潜力的类药分子的易相互作用部分。
