LAUSR

Abstract As a kind of potential anticancer compounds, Cyclin-dependent kinase (CDK) inhibitors have receved great attention in recent years. In order to deep research the bioactivity and corresponding key influence factors of CDK8/19 inhibitors on molecular level, quantum chemistry and 3D-QSAR have been performed on 64 molecules based on pyridine ring scaffold. Two high predictive QSAR models have been built, in which both the CoMFA model (q2 = 0.69, r2 = 0.98) and CoMSIA model (q2 = 0.61, r2 = 0.98) have displayed quite good external predictablility on test set with excellent values of r p r e d 2 (0.94 and 0.97). In these models, the steric, electrostatic and hydrophobic fields have played key roles on bioactivity. Docking simulation has been carried out to further investigate possible binding modes of compounds into the active site of CDK8 (PDB. 5I5Z), the results show that some high bioactivity molecules are quite well embedded in the active pocket. Nitrogen-atom of pyridine ring and some other groups (ie. NH, CO, SO. NH, CO, SO) have formed medium strength hydrogen bonds (1.5 A to 2.2 A) with the N, H, O atoms of the protein. The geometric structures of the inhibitor molecules have been changed differently during the processes of docking, surflex-dock has confirmed the acting force stability of predicted molecules in the protein. Our method and results can be helpful for finding new targets and developing new drugs.