Wargasetia TL et al. (2021), Bioinformatics Study of Sea Cucumber Peptides a...

ECB-ART-49047

Cancer Inform 2021 Jul 13;20:11769351211031864. doi: 10.1177/11769351211031864.

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Bioinformatics Study of Sea Cucumber Peptides as Antibreast Cancer Through Inhibiting the Activity of Overexpressed Protein (EGFR, PI3K, AKT1, and CDK4).

Wargasetia TL , Ratnawati H , Widodo N , Widyananda MH .

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Breast cancer is the most common type of cancer in women globally. The overexpressed proteins, including EGFR, PI3K, AKT1, and CDK4, have a role in the growth of breast cancer cells. The 3D peptide structure of sea cucumber Cucumaria frondosa was modeled and then docked with EGFR, PI3K, AKT1, and CDK4 proteins using AutoDock Vina software. The docking result, which has the best binding affinity value, is continued with molecular dynamics simulation. The docking results showed that all peptides bind to the active sites of the four proteins. WPPNYQW and YDWRF peptides bind to proteins with lower binding affinity values than positive controls. The four proteins were in a stable state when complexed with the WPPNYQW peptide, which was seen from the RMSD and RMSF value. PI3K-YDWRF and AKT1-YDWRF complexes are stable, characterized by high RMSD values and increased volatility in several amino acids. WPPNYQW peptide has high potential as an antibreast cancer agent because it binds to the active sites of the four proteins with low binding affinity values and stable interactions. Meanwhile, the YDWRF peptide interacts with the four proteins with low binding affinity values, but the interaction is only stable on PI3K and AKT1 proteins.

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	Figure 1. All peptides bind to the active site of EGFR (A), PI3K (B), AKT1 (C), and CDK proteins (D). The active site of the protein is marked in yellow. The docking results showed that all peptides have potential as competitive inhibitors because they bind to the protein on the active site.AKT1 indicates Protein Kinase B1; CDK4, Cyclin Dependent Kinase 4; EGFR, Epidermal Growth Factor Receptor; PI3K, Phosphatidylinositol-3 kinase.
	Figure 2. WPPNYQW (orange) and YDWRF (green) peptides bind to EGFR (A), PI3K (B), AKT1 (C), and CDK4 (D) on the same side as the inhibitor. WPPNYQW and YDWRF peptides have a similar binding mode to the inhibitor indicating the peptides have the potential to act as protein inhibitors.AKT1 indicates Protein Kinase B1; CDK4, Cyclin-Dependent Kinase 4; EGFR, Epidermal Growth Factor Receptor; PI3K, Phosphatidylinositol-3 kinase.
	Figure 3. The stability of protein-ligand complex interactions can be seen from RMSD values. (A) The RMSD values of the EGFR-inhibitor, EGFR-WPPYQW, and EGFR-YDWRF complexes tend to be stable. (B) The RMSD values of the PI3K-inhibitor, PI3K-WPPYQW, and PI3K-YDWRF complexes are stable during the simulation. (C) The RMSD values of the AKT1-inhibitor, AKT1-WPPNYQW, and AKT1-YDWRF complexes are stable during the simulation. (D) The RMSD value of the CDK4-WPPNYQW complex is more stable than the CDK4-inhibitor and CDK4-YDWRF. The CDK4-YDWRF complex tends to be unstable because of its high RMSD value. (E) RMSD peptides and target proteins.AKT1 indicates Protein Kinase B1; CDK4, Cyclin-Dependent Kinase 4; EGFR, Epidermal Growth Factor Receptor; PI3K, Phosphatidylinositol-3 kinase; RMSD, root mean square deviation.
	Figure 4. The stability of each amino acid residue during the simulation can be seen from the RMSF value. (A) Val1010 and Val1011 residues of the EGFR-YDWRF complex have high flexibility. (B and C) The residues on the PI3K-Ligands and AKT1-Ligands complexes tend to be stable during simulation. (D) Pro245, Arg246, Gly247, and Ala248 residues of the CDK4-YDWRF complex have high flexibility. High flexibility indicates instability of residue.AKT1 indicates Protein Kinase B1; CDK4, Cyclin-Dependent Kinase 4; EGFR, Epidermal Growth Factor Receptor; PI3âK, Phosphatidylinositol-3 kinase; RMSF, root mean square fluctuation.
	Figure 5. The stability of the complex structure can be seen from the number of hydrogen bonds during the simulation. The number of hydrogen bonds in EGFR-peptides (A), PI3K-peptides (B), AKT1-peptides (C), and CDK4-peptides (D) were not significantly different from proteins-inhibitors. These results indicate the structural stability of the protein-peptide complexes.AKT1 indicates Protein Kinase B1; CDK4, Cyclin-Dependent Kinase 4; EGFR, Epidermal Growth Factor Receptor; PI3K, Phosphatidylinositol-3 kinase.
	Figure 6. The molecular dynamic binding energy represents the stability of the protein-ligand interaction during the simulation. The more positive the molecular dynamic binding energy value, the more stable the protein-ligand interaction. The molecular dynamic binding energy values of EGFR-peptides (A), PI3K-peptides (B), AKT1-peptides (C), and CDK4-peptides were lower than proteins-inhibitors.AKT1 indicates Protein Kinase B1; CDK4, Cyclin-Dependent Kinase 4; EGFR, Epidermal Growth Factor Receptor; PI3K, Phosphatidylinositol-3 kinase.

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