Plant Biotechnology Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 220025, India.
J Chem Inf Model. 2023 Apr 24;63(8):2331-2344. doi: 10.1021/acs.jcim.2c01315. Epub 2023 Apr 6.
Heterocyclic compounds have a prominent role in medicinal chemistry and drug design. They are not only useful as medicinally active compounds but also as a modular structural scaffold for drug design. Therefore, heterocycles are present in many ligands that exhibit a broad spectrum of biological activities. Pyazolopyrimidines are nitrogen heterocycles and are part of many biologically active compounds and marketed drugs. This study examines the non-covalent interactions between the pyrazolopyrimidine rings and receptor proteins through data mining and analysis of high-resolution crystal structures deposited in the Protein Data Bank. The Protein Data Bank contains 471 crystal structures with pyrazolopyrimidine derivatives as ligands, among which 50% contains 1-pyrazolo[3,4-]pyrimidines (Pyp1), while 38% contains pyrazolo[1,5-] pyrimidines (Pyp2). 1-Pyrazolo[4,3-]pyrimidines (Pyp3) are found in 11% of the structures, and no structural data is available for pyrazolo[1,5-]pyrimidine isomers (Pyp4). Among receptor proteins, transferases are found in most examples (67.5%), followed by hydrolases (13.4%) and oxidoreductases (8.9%). Detailed analysis of structures to identify the most prevalent interactions of pyrazolopyrimidines with proteins shows that aromatic π···π interactions are present in ∼91% of the structures and hydrogen bonds/other polar contacts are present in ∼73% of the structures. The centroid-centroid distances () between the pyrazolopyrimidine rings and aromatic side chains of the proteins have been retrieved from crystal structures recorded at a high resolution (data resolution <2.0 Å). The average value of in pyrazolopyrimidine-protein complexes is 5.32 Å. The information on the geometric parameters of aromatic interactions between the core pyrazolopyrimidine ring and the protein would be helpful in future in silico modeling studies on pyrazolopyrimidine-receptor complexes.
杂环化合物在药物化学和药物设计中具有重要作用。它们不仅作为药用活性化合物有用，而且作为药物设计的模块化结构支架也很有用。因此，杂环存在于许多表现出广泛生物活性的配体中。吡唑并嘧啶是氮杂环，是许多具有生物活性的化合物和市售药物的一部分。本研究通过数据挖掘和分析存储在蛋白质数据库中的高分辨率晶体结构，研究了吡唑并嘧啶环与受体蛋白之间的非共价相互作用。蛋白质数据库包含 471 个含有吡唑并嘧啶衍生物作为配体的晶体结构，其中 50%包含 1-吡唑并[3,4-d]嘧啶（Pyp1），而 38%包含吡唑并[1,5-d]嘧啶（Pyp2）。在结构中发现 11%为 1-吡唑并[4,3-d]嘧啶（Pyp3），而吡唑并[1,5-d]嘧啶异构体（Pyp4）没有结构数据。在受体蛋白中，转移酶在大多数情况下（67.5%）发现，其次是水解酶（13.4%）和氧化还原酶（8.9%）。详细分析结构以确定吡唑并嘧啶与蛋白质的最常见相互作用表明，芳香π···π相互作用存在于约 91%的结构中，氢键/其他极性相互作用存在于约 73%的结构中。从以高分辨率（数据分辨率<2.0 Å）记录的晶体结构中检索到吡唑并嘧啶环和蛋白质芳香侧链之间的质心-质心距离（）。吡唑并嘧啶-蛋白质复合物中值的平均值为 5.32 Å。关于核心吡唑并嘧啶环与蛋白质之间芳族相互作用的几何参数的信息将有助于未来吡唑并嘧啶-受体复合物的计算机建模研究。
