Cyclic peptides as an inhibitor of metastasis in breast cancer targeting MMP-1: Computational approach

Matrix metalloproteinases-1 is recognized as a potential target of tumors and cancer for their role in breaking down collagen and extracellular matrix proteins. Our study screened 51 peptides against MMP-1 to find potent inhibitors for preventing breast cancer metastasis. Since cyclic peptides have higher selectivity and stability than linear peptides, we have focused our study on peptides with a cyclic structure as an MMP-1 inhibitor. We used an in-silico approach to design cyclic peptides and illustrated their activity as specific non-zinc binding inhibitors of MMP-1. Peptide cyclization, induced-fit docking (IFD), molecular dynamics simulation, and binding free energy (MM/GBSA) calculation were applied to evaluate the activity of peptides to inhibit MMP-1. Among the 51 peptides, we selected four peptides based on their docking score, binding affinity, and interacting residues. Complex 35, 36, 37, and 51 achieved highest docking scores of −215.37, −215.71, −195.56, and −208.08 kcal/mol, respectively. From the molecular dynamic simulation, we found three complexes (35, 36, and 37) with a stable structural conformation in terms of APO protein for 500 ns? Complexes 35, 36, 37 and 51 exhibited an average RMSD value of 2.45 ± 0.19, 3.39 ± 0.39, 2.03 ± 0.47, 2.60 ± 0.30 Å, respectively. The MM/GBSA free energy analysis of protein-peptide complex, complex 35, 36, and 37 show the greater MM/GBSA result consisting of the average value of −54.61 ± 0.45, −66.57 ± 0.38, and −43.57 ± 0.45 kJ/mol. These findings can facilitate the rational design and modifications of selective peptide inhibitors targeting the catalytic domain of MMP-1