Design and screening of FAK, CDK 4/6 dual inhibitors by pharmacophore model, molecular docking, and molecular dynamics simulation

Focal adhesion kinase (FAK) is one kind of tyrosine kinases that modulates integrin and growth factor signaling pathways, which is a promising therapeutic target because of involving in the migration, proliferation and survival of cancer cell. Overexpression and amplification of cyclin-dependent kinase 4/6 (CDK4/6) occur in many cancers and may be the cause of resistance to CDK4/6 inhibitors in preclinical models. The latest research shows that the combination of FAK and CDK4/6 can be dually targeted to enhance the antitumor effects. In this study, FAK and CDK4/6 dual target inhibitors were designed by computer-aided drug design. Seven million molecules were screened by the pharmacophore model and molecular docking. Finally, 6 compounds were obtained. Molecular dynamics simulation of compound 1, 2 and 3 showed that it has good binding stability to both receptors. According to the binding modes of compound 1 with two receptors, corresponding modifications were made, and 7 novel designed compounds were obtained. The docking energy of these novel designed compounds were lower than that of compound 1, and they can be tested in future.