A Computational Perspective into Binding Mechanism of a potent FAK Inhibitor as Anticancer Drug Candidate: Insights from Molecular Dynamics Simulations

Focal adhesion kinase (FAK) is an important non-receptor tyrosine kinase (nRTK) with crucial role in primary cell functions. Fundamental cellular processes, such as migration, adhesion, proliferation, and survival, are regulated by FAK. The tumorigenesis of FAK is very important since it is overexpressed in advanced cancers, causes malignant features and induces cancer metastasis. The available evidence proposes FAK as a promising target for cancer therapy. At the moment, there are no FAK inhibitors (FAKIs) in the market but several small molecule FAKIs have been developed and a few of them entered into clinical studies as anticancer agents. In spite of these achievements, development of selective and potent FAKIs may be partly hampered by the lack of crystallographic or structural data. This limitation could be resolved through proposing robust ligand–protein binding models to design new FAKIs. GSK2256098 is a small molecule ATP-competitive FAKI that undergoes clinical trials as a monotherapy or in combination with other medications against advanced solid tumors. GSK2256098 have been proven to be a selective and potent agent (IC[Formula: see text] 0.4 nM) with respect to other clinical candidates. With regard to appropriate characteristics, this molecule is particularly amenable for performing computational modeling studies. In this study, we try to propose an applicable binding model of GSK2256098 inside the FAK kinase domain. For this purpose, molecular docking, all-atom 200-ns molecular dynamics simulations and free-energy-calculation methods were applied as consecutive modeling techniques. Atomic insight and dynamic evolution of the system were used to attain a stable binding mode and infer chemical interactions of GSK2256098 inside the kinase domain of FAK. Although complementary investigations need to be conducted, obtained results may offer a structural basis for the development of potent and selective FAKIs.