Abstract:

A novel and reliable docking model based on the protein structure of cyclin dependent kinase 7 (CDK7) for CDK7 inhibitors was developed using LigandFit module within Discovery Studio 2.1 package. Receiver operating characteristic curves (ROC) were applied as a method of validation to evaluate the accuracy of the established model. LigScore2 was selected as the best score function. The area under curve (AUC) of the ROC curve was 0.95. Compounds designed by our group were docked with CDK7 to study the binding mode between the target molecules and the receptor protein CDK7. Two compounds, namely 16 and 17, with favorable scores from the docking studies were selected for synthesis and required a thirteen-step route but they were obtained in moderate to good yields. The two synthesized compounds were then evaluated for their in vitro cytotoxic activities against five human cancer cell lines including human acute promyelocytic leukemia cells (HL60), human nasopharynx carcinoma cells (KB), human hepatoma cells (SMMC-7721), human colon adenocarcinoma cells (HCT-116), and human lung cancer cells (A549). Both tested compounds showed potent cytotoxic activities with IC50 values ranging from 0.84 to 19.70 μmol·L-1 . Compound 16 showed the most potent antitumor activity against HL60 human cancer cell lines with IC50 value of 0.84 μmol·L-1.

Key words: Molecular docking, CDK7 inhibitor, LigandFit module, LigScore2 score function, Synthesis, Antitumor activity