Homology Modeling, Molecular Docking, and 3D-QSAR of Indirubin Analogues as CDK1 Inhibitors

The abnormal expression of cyclin-dependent kinase 1 (CDK1) leads to stagnation of the G2 phase and a variety of tumors. Therefore, CDK1 has been reported recently as an ideal cell cycle target for cancer drug discovery. In this paper, we use the cell division control protein 2 homolog as a template to homologically model the protein of CDK1 that is subsequently docked with the inhibitors of indirubin analogues. Three molecular alignment methods were used, and the corresponding three-dimensional quantitative structure-activity relationship (3D-QSAR) models were built using the comparative molecular field analysis (CoMFA) protocol in Sybyl 7.1 and the 3D-QSAR protocol (abbreviated for DS) in Discovery Studio 3.0. It was found that the molecular alignment method combining molecular docking with public template is most suitable for building the 3D-QSAR models, and shows the best calculated results (CoMFA: q(2)=0.681, r(2)=0.909, and r(pred.)(2)=0.836; DS: q(2)=0.579, r(2)=0.971, and r(pred.)(2)=0.795, where q(2) denotes the cross-validated correlation coefficient and r(2) denotes the non-cross-validated correlation coefficient). This paper may provide significant theoretical foundation for designing novel CDK1 inhibitors by carrying out structural modifications of indirubin analogues.