Protein kinases control diversity of biochemical processes in human organism. Checkpoint 1 kinase (Chk1) is an important element of the checkpoint signalling pathways and is responsible for DNA damage repair. Hence, this kinase plays an essential role in cancer cells survival and has become an important target for anticancer agents. Our previous investigations showed that some arylsulphonyl indazole derivatives displayed anticancer effect in vitro. In the present study, in order to verify possibility of interactions of pyrazole and indazole derivatives with Chk1, we focused on the docking of selected tosyl derivatives of indazole and condensed pyrazole 1–7 to the Chk1 pocket, analysis of interactions involving optimized ligand–protein system using DFT formalism, and estimation of the interaction enthalpy of the ligand–protein complex by applying the PM7 method. The estimation of binding affinity seems to indicate that the indazole 5-substituted with 3,5-dimethylpyrazole 4 and condensed pyrazoloquinoline derivative 7 fit the best to the Chk1-binding pocket. The values of the energy of interaction, i.e. the enthalpy change (ΔH_int), were between − 85.06 and − 124.04 kcal mol⁻¹ for the optimized ligand–Chk1 complexes. The relaxation of the ligands within the complexes azole–protein as well as the distribution of hydrogen contacts between the ligands and kinase pocket amino acids was also analysed using molecular dynamics as a supporting method.

Presentation of methods used to describe the interactions between arylsulphonyl pyrazole derivatives and Chk1 kinase

中文翻译：

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选择的芳基磺酰基吡唑衍生物作为潜在的Chk1激酶配体-计算研究。

蛋白激酶控制着人类有机体中生物化学过程的多样性。Checkpoint 1激酶（Chk1）是Checkpoint信号通路的重要组成部分，负责DNA损伤修复。因此，该激酶在癌细胞存活中起重要作用，并已成为抗癌剂的重要靶标。我们以前的研究表明，一些芳基磺酰基吲唑衍生物在体外具有抗癌作用。在本研究中，为了验证与Chk1的吡唑和吲唑衍生物的相互作用的可能性，我们专注于吲唑选定甲苯磺酰基衍生物的对接和冷凝吡唑1 - 7到Chk1口袋，使用DFT形式论分析涉及优化的配体-蛋白质系统的相互作用，并通过应用PM7方法估算配体-蛋白质复合物的相互作用焓。结合亲和力的估计似乎表明被3,5-二甲基吡唑4和稠合的吡唑并喹啉衍生物7 5取代的吲唑最适合与Chk1结合的口袋。相互作用能的值，即焓变（ΔH _int）介于-85.06和-124.04 kcal mol ^-1之间优化的配体– Chk1复合物。还使用分子动力学作为支持方法，分析了配体唑-蛋白质中配体的弛豫以及配体与激酶口袋氨基酸之间的氢接触分布。

介绍用于描述芳基磺酰基吡唑衍生物与Chk1激酶之间相互作用的方法