*4.16. Dynamics Molecular Docking*

The molecular docking study was conducted with the PyRx v0.8 [52]. VEGFR2 (PDB ID:3B8Q) was obtained from the RCSB Protein Data Bank (https://www.rcsb.org/, accessed on 1 March 2022). All polar hydrogens of the protein crystals were added, and the solvent water molecules were removed and converted into the pdbqt format. All compounds were obtained from the PubChem database as the sdf format files, and saved in the pdbqt format after conversion to an energy-minimized form using Pthe yRx v0.8. Docking was performed in the PyRx v0.8 with the following docking box parameters center\_x 39.0 center\_y 33.4 center\_z 14.5 size\_x 19.4 size\_y 27.7 size\_z 17.4. The results were visualized with the Pymol v2.4.1.

Desmond software package (developed at D. E. Shaw Research) was used to investigate the molecular interactions. In the molecular dynamics simulations, the complexes were placed into an automatically calculated cube box in which the complexes were modeled separately using transferable interatomic potential with three points model (TIP3P). The optimization of the models was further accomplished by optimized potentials for liquid simulations 4 (OPLS4). The system was neutralized by the addition of NaCl to make the system isotonic. A Nosehoover thermostat was used to provide a temperature of 300 k. The Martyna–Tobias–Klien barostat was used to maintain a pressure of 1.01325 bars. The total time for the molecular dynamics simulation was 50 ns. Ligand–protein interactions were simulated using the Interaction Diagram tool in the Desmond package. The Desmond package was used to generate the RMSD and RMSF of the proteins, and the interactions were further analyzed.
