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

Abstract

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.

Identification of abemaciclib derivatives targeting cyclin-dependent kinase 4 and 6 using molecular dynamics, binding free energy calculation, synthesis, and pharmacological evaluation

“…In addition, the T-loop for protein kinase has diversified conformations, with open, closed, and intermediate conformations. For instance, human FAK may exhibit an open or closed T-loop conformation while binding with FAK inhibitors ( Shi et al, 2022a ; Guo et al, 2022 ). However, some inhibitors, such as the pan-kinase inhibitor bosutinib-bound SIK2, can also bind to the protein kinase with conformational plasticity in the active pocket of the T-loop ( Shi et al, 2022c ).…”

Interactions between curcumin and human salt-induced kinase 3 elucidated from computational tools and experimental methods

“…The conformation of DFG motif may affect the binding models for curcumin and SIK3. Moreover, the DFG motif of human FAK is an important region, which improves the affinity of the FAK inhibitors by forming a hydrogen bond between the DFG motif and inhibitors ( Shi et al, 2022a ). This indicates that the DFG motif of SIK3 can also be employed to increase the affinity between curcumin and SIK3 by replacing the 4-hydroxy-3-methoxy phenyl group of curcumin.…”

“…However, some type-I inhibitors, such as dasatinib (Shi et al, 2021a), bosutinib (Shi et al, 2022b), MRT67307 (Shi et al, 2021b), MRT199665 (Shi et al, 2021b), KIN112 (Shi et al, 2021b), and HG-9-91-01 (Shi et al, 2021b), exhibit diverse T-loop conformations while binding with SIK2. Such diverse conformations of the of T-loop have also been reported for type-I inhibitors binding with human FAK (Shi et al, 2022a). Therefore, we speculated that curcumin may also bind with human In this study, we constructed SIK3-C with closed T-loop and SIK3-O with open T-loop for SIK3 using HM, which were based on the crystal structures of MARK family.…”

Volatile Organic Compounds Adsorption Capacities of Zeolite/Activated Carbon Composites Formed by Electrostatic Self-Assembly

“…With the development of computer technology, the application range and accuracy of simulations have been greatly improved and have been used to quantify the bond strengths between different substances. For example, Shi and colleagues calculated the binding free energies for several small-molecule inhibitors and focal adhesion kinase by using the molecular mechanics generalized Born surface area method. Zeng et al simulated the molecular dynamics for interactions between a graphene oxide/graphene composite and alkali metal ions with Materials Studio and then calculated the interaction energy and radial distribution function.…”