Design and In Silico Evaluation of a Novel Cyclic Disulfide-Rich anti-VEGF Peptide as a Potential Antiangiogenic Drug

The vascular endothelial growth factor (VEGF) signaling pathway has a crucial role in regulating tumor angiogenesis. VEGF-A shows prominent interaction with the VEGF receptor-1 and VEGF receptor-2 on the membrane of the endothelial cells. The current study aimed to design and model an anti-VEGF peptide based on VEGFR2 binding regions. The effective amino acid sequences in the interaction of VEGF-A and VEGFR-2 were investigated using Chimera, SPDBV and PyMOL software. The VEGF binding sites on the receptor were determined and used as the basis for peptide design. This sequence was then subjected to random mutagenesis, and the binding affinity of resultant peptides analyzed by Hex 8.0.0 and ClusPro software. Then, GROMACS v5.0.6 has been used for Molecular Dynamics (MD) simulation and assessing the stability of target-ligand complexes. Finally, the chosen peptide with the highest affinity was grafted into two loops of SFTI-1 (sunflower trypsin inhibitor-1) and MCoTI-II (Momordica cochinchinensis trypsin inhibitor-II) frameworks for improving the peptide stability. Among the 18 peptides from the second library, four peptides were opted, of which NGIDFNRDKFLFL showed the highest affinity with a total energy of − 742 kcal/mol. We found that this peptide can bond to the VEGF and block VEGF binding to VEGFR2. The RMSD, RMSF, and H-bonds analysis verified the docking results. The peptide grafted into loop 1 of SFTI-1 increased the peptide-VEGF binding affinity compared to peptide alone. The results showed that in silico design could be used for the identification of efficient anti-angiogenic peptides for potential application in antiangiogenic therapies.