Molecular Docking, Molecular Dynamics Simulations, and Free Energy Calculation Insights into the Binding Mechanism between VS-4718 and Focal Adhesion Kinase

by Selleckchem | Jun 21 2023

Focal adhesion kinase (FAK) is a 125 kDa nonreceptor tyrosine kinase that plays an important role in many carcinomas. Thus, the targeting of FAK by small molecules is considered to be promising for cancer therapy. Some FAK inhibitors have been reported as potential anticancer drugs and have entered into clinical development; for example, VS-4718 is currently undergoing clinical trials. However, the lack of crystal structural data for the binding of VS-4718 with FAK has hindered the optimization of this anticancer agent. In this work, the VS-4718/FAK interaction model was obtained by molecular docking and molecular dynamics simulations. The binding free energies of VS-4718/FAK were also calculated using the molecular mechanics generalized Born surface area method. It was found that the aminopyrimidine group formed hydrogen bonds with the C502 residue of the hinge loop, while the D564 residue of the T-loop interacted with the amide group. In addition, I428, A452, V484, M499, G505, and L553 residues formed hydrophobic interactions with VS-4718. The obtained results therefore provide an improved understanding of the interaction between human FAK and VS-4718. Based on the obtained binding mechanism, 47 novel compounds were designed to target the adenosine 5'-triphosphate-binding pocket of human FAK, and ensemble docking was performed to assess the effects of these modifications on the inhibitor binding affinity. This work is also expected to provide additional insights into potential future target design strategies based on VS-4718.

Comments:

The passage describes a research work that focuses on the interaction between the anticancer drug VS-4718 and focal adhesion kinase (FAK), a nonreceptor tyrosine kinase implicated in carcinomas. FAK inhibitors, such as VS-4718, have shown promise in cancer therapy, but the lack of crystal structural data for the binding between VS-4718 and FAK has hindered the optimization of this drug.

To overcome this limitation, the researchers employed molecular docking and molecular dynamics simulations to generate a model of the VS-4718/FAK interaction. They also calculated the binding free energies using the molecular mechanics generalized Born surface area method. Through their analysis, they discovered specific interactions between VS-4718 and key residues in FAK.

The aminopyrimidine group of VS-4718 formed hydrogen bonds with the C502 residue located in the hinge loop, while the amide group interacted with the D564 residue in the T-loop of FAK. Furthermore, hydrophobic interactions were observed between VS-4718 and several other residues, including I428, A452, V484, M499, G505, and L553.

With a better understanding of the binding mechanism between human FAK and VS-4718, the researchers designed 47 new compounds that targeted the adenosine 5'-triphosphate-binding pocket of FAK. Ensemble docking was performed to assess the impact of these modifications on the binding affinity of the inhibitors. This research provides valuable insights into the interaction between VS-4718 and FAK, and it may also guide future strategies for designing potential FAK inhibitors based on the knowledge gained from studying VS-4718.