Selected arylsulphonyl pyrazole derivatives as potential Chk1 kinase ligands—computational investigations

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. [Figure: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00894-020-04407-3) contains supplementary material, which is available to authorized users.