Molecular modeling studies of novel naphthyridine and isoquinoline derivatives as CDK8 inhibitors

Cell cycle is an important part of cellular activities. The selective inhibition of cyclin-dependent kinases (CDK) activity in tumor cells can lead to continuous cell proliferation. Thirty-nine CDK8 inhibitors were systematically investigated on the basis of a three-dimensional quantitative structure-activity relationship (3D-QSAR). Models for comparative molecular field analysis (q2=0.64, r2=0.98) and comparative molecular similarity index analysis (q2=0.609, r2=0.952) were obtained. Contour maps illustrated that bioactivity of inhibitors is most affected by steric, electrostatic, hydrogen bond donor, and receptor interactions of molecular groups. Twenty new CDK8 inhibitors (DS01-DS20) were designed based on the contour maps. The results of ADME prediction illustrated that the designed compounds had potential druggability. The binding mode between a ligand and receptor was explored through molecular docking and molecular dynamics. Results revealed that the hydrogen bond interaction with residue LYS52 remarkably affected the activity of these compounds. Further analysis indicated that the introduction of fluorine to an amino naphthyridine ring of compound 28 contributes to the improvement of molecular activities. Pharmacophore-based virtual screening and Surflex-Sim in the ZINC database of 1,30,000 molecules demonstrated that 14 compounds with an indazole ring might be antitumor inhibitors. 3D-QSAR, molecular docking, molecular dynamics and pharmacophore results are consistent. These findings can be used as a reference for the design and discovery of new CDK8 inhibitors that can reduce design errors.Communicated by Ramaswamy H. Sarma.