Harnessing the Therapeutic Potential of Pomegranate Peel-Derived Bioactive Compounds in Pancreatic Cancer: A Computational Approach

Abstract

Background/Objectives: Pomegranate (Punica granatum) peel, often discarded as waste, contains abundant bioactive compounds such as polyphenols, vitamins, flavonoids, tannins, anthocyanins, and many more. This contributes to remarkable bioactivities, including anticancer, anti-inflammatory, antioxidant, antibacterial, and antifungal properties. Pancreatic cancer is a deadly cancer with a 9% survival rate. Its aggressiveness, invasiveness, quick metastasis, and poor prognosis significantly decrease the survival rate. Thus, we aim to explore pomegranate peel as a possible alternative medication for treating pancreatic cancer through virtual methods. Methods: Firstly, bioactive compounds were collected from multiple databases and screened for oral bioavailability (OB) ≥ 0.3 and drug likeness (DL) ≥ 0.18 scores. Simultaneously, network pharmacology was employed to extract the most probable targets for pancreatic cancer. Further computational analyses were performed, including molecular docking, molecular dynamics simulation, and in silico pharmacokinetics evaluation. Results: Consequently, the top 10 key targets from network analysis were AKT1, IL6, TNF, SRC, STAT3, EGFR, BCL2, HSP90AA1, HIF1A, and PTGS2. However, only AKT1, EGFR, BCL2, HSP90AA1, and PTGS2 exhibited strong binding affinities with pomegranate compounds, which are significantly declared in affected cells to enhance cancer progression. Outcomes from molecular dynamics simulations, particularly RMSD, RMSF, hydrogen bonding, and radius of gyration (Rg), confirmed stable interactions between 1-O-Galloyl-beta-D-glucose, epicatechin, phloridzin, and epicatechin gallate with respective target proteins. Conclusions: This suggests that pomegranate peels hold anticancer bioactive compounds for treating pancreatic cancer. Surprisingly, most compounds adhere to Lipinski's and Pfizer's rules and display no toxicity. However, as this study relies entirely on computational methods, experimental validation is necessary to confirm these findings and assess real-world efficacy and potential side effects.

Keywords: molecular docking; molecular dynamics simulation; network pharmacology; pancreatic cancer; pomegranate peel.

Figure 1

Pomegranate–Pancreatic Cancer. (a) Top 10 compound targets highlighted in yellow, red, orange and target proteins are highlighted in blue colors; (b) Intersection of target genes between disease and pomegranate.

Figure 2

Protein–protein interaction network. (a) Interaction nodes and edges; (b) Top 30 gene interactions obtained from (a); (c) Top 10 genes responsible for PC management.

Figure 3

GO and KEGG analysis. (a) Top 10 Go enrichment terms; (b) The histogram diagram of genes in each pathway; (c) Top 30 KEGG pathways involved in PC; (d) Sanky and Bubble diagram of KEGG pathways for hub targets.

Figure 4

Pancreatic cancer pathways and key proteins highlighted in red color.

Figure 5

Molecular interactions between protein and ligands. (a) 1-O-Galloyl-beta-D-glucose compound interaction with PTGS2 protein (PDB ID: 5F19); (b) Epicatechin compound interaction with HSP90AA1 protein (PDB ID: 6TN5); (c) Phloridzin compounds interaction with EGFR protein (PDB ID: 8A27); (d) Epicatechin gallate interaction with EGFR protein (PDB ID:8A27); (e) 1-O-Galloyl-beta-D-glucose compound interaction with AKT1 protein (PDB ID:4GV1).

Figure 6

RMSD of all compounds. (a) 1-O-Galloyl-beta-D-glucose with PTGS2 protein; (b) Epicatechin with HSP90AA1 protein; (c) Phloridzin with EGFR protein; (d) Epicatechin gallate with EGFR protein; (e) 1-O-Galloyl-beta-D-glucose with AKT1 protein.

Figure 7

RMSF (a–e) illustrates the protein–ligand interaction, highlighting (green lines) the key residues that are involved in the stabilizing ligand within the binding pocket of the protein. (a) 1-O-Galloyl-beta-D-glucose with PTGS2 protein; (b) Epicatechin with HSP90AA1 protein; (c) Phloridzin with EGFR protein; (d) Epicatechin gallate with EGFR protein; (e) 1-O-Galloyl-beta-D-glucose with AKT1 protein.

Figure 8

Protein–ligand contact: Green (H-bonds); Grey (Hydrophobic); Pink (Ionic); Blue (Water bridge); (a) 1-O-Galloyl-beta-D-glucose with PTGS2 protein; (b) Epicatechin with HSP90AA1 protein; (c) Phloridzin with EGFR protein; (d) Epicatechin gallate with EGFR protein; (e) 1-O-Galloyl-beta-D-glucose with AKT1 protein.