Abstract
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 (ΔHint), 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.Graphical Presentation of methods used to describe the interactions between arylsulphonyl pyrazole derivatives and Chk1 kinase
Highlights
Chemotherapy is one of the major treatments of cancer and often relies on DNA damage of fast proliferating cancer cells
Checkpoint kinase 1 is a pivotal element of the checkpoint signalling involving DNA damage response
As the DDR occurs in reaction to DNA destruction by cytotoxic agents and radiation, checkpoint kinase 1 (Chk1) is a potential target for kinase inhibitors [52]
Summary
Chemotherapy is one of the major treatments of cancer and often relies on DNA damage of fast proliferating cancer cells. The cancer cell response to such damage (DNA damage response, DDR) is activation of the S- and G2/M-Phase checkpoints that leads to effective repair of DNA and cell survival. The above checkpoints are controlled by checkpoint kinase 1 (Chk1), a serine/threonine kinase with selfprotection function [1]. Overexpression of Chk has been found to relate to pulmonary arterial hypertension (PAH), a progressive vascular remodelling of distal arteries, resulting in severe elevation of pulmonary artery pressure [3]. It has been shown that smooth muscle cells of these arteries exhibit cancer-like properties, i.e. fast proliferation and resistance to apoptosis. Chk might be an attractive target for the therapy of patients with PAH
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