Design of novel focal adhesion kinase inhibitors using 3D-QSAR and molecular docking

Focal adhesion kinase (FAK) plays a primary role in regulating the activity of many signaling molecules. Increased FAK expression has been implicated in a series of cellular processes, including cell migration and survival. Inhibiting the activity of FAK for cancer therapy is currently under investigation. Hence, FAK and its inhibitors have been the subject of intensive research. To understand the structural factors affecting inhibitory potency, molecular docking and 3D-QSAR modeling were studied in this project. CoMFA and CoMSIA methods were used for deriving 3D-QSAR models, which were trained with 78 compounds and then were evaluated for predictive ability with additional 19 compounds. Two substructure-based 3D-QSAR models, including CoMFA model (r2 = 0.930; q2 = 0.629) and CoMSIA model (r2 = 0.952; q2 = 0.586), had a good quality to predict the biological activities of new compounds. Meanwhile, using the flexible docking strategy, two docking-based 3D-QSAR models (CoMFA with r2 = 0.914; q2 = 0.594; CoMSIA with r2 = 0.914; q2 = 0.524) were also constructed. The structure–activity relationship has been illustrated clearly by the contour maps gained from the 3D-QSAR models in combination with the docked binding structures. All the results indicated that it might be useful in the rational design of novel FAK inhibitors.