In Silico Evaluation of Pistachio Peel-Derived Phenolic Compounds as Anticancer Agents Against TLR۴ and STAT۳ in Breast Cancer

Background and Objective: Breast cancer is the most common type of cancer and a leading cause of cancer-related mortality among women. Increased oxidative factors and decreased antioxidants are primary contributors to the development of this cancer. Pistachio peel is rich in phenolic compounds and serves as an affordable source of antioxidants, potentially making it an effective option for combating cancer cells. The TLR۴ gene, a cell surface receptor involved in innate immune responses, is also implicated in cancer progression. With the onset of cancer and the increase in inflammatory and pro-inflammatory factors, TLR۴ promotes cancer advancement by overproducing pro-inflammatory cytokines through forward signaling pathways. Another regulatory gene in cancer that influences tumor promotion through inflammation is STAT۳. STAT۳ is an oncoprotein that regulates cell survival, proliferation, and metastasis in breast cancer signaling pathways. Its overexpression in breast epithelial cells contributes to tumor progression. This study aims to evaluate the effect of pistachio peel on the TLR۴ and STAT۳ genes in breast cancer. Materials and Methods: Bioinformatics analyses were employed in this descriptive-analytical study. The three-dimensional structures of certain active compounds in pistachio peel and the target genes were retrieved from the PubChem, PDB, and Uniprot databases, respectively. After optimizing the energy of proteins and ligands and preparing them using Chimera software, molecular docking of protein-ligand interactions was performed using AutoDock (v۴.۲.۶). The physicochemical properties and biological activities of the compounds were predicted using Swiss ADME. Results: The findings of this study indicate that the active compounds in pistachio peel possess favorable physicochemical properties and lack toxicity. Molecular docking simulations showed acceptable binding energies for the interactions between the ligands (catechin, epicatechin, and isoquercetin) and the active site of the STAT۳ protein, with binding energies of -۴.۴۶, -۴.۲۸, and -۴.۵۱, respectively. Catechin demonstrated a stronger affinity for binding with amino acids ASN۶۴۷, GLU۶۴۴, and TYR۶۴۰, epicatechin with ASN۴۴۷, and Isoquercetin with GLU۶۴۴ and LYS۶۵۸. Additionally, an acceptable binding energy of -۴.۸۱ was observed for the catechin ligand with the active site of the TLR۴ protein, forming hydrogen bonds with LYS۳۶۲ and TYR۱۰۲. Conclusion: Based on the results from bioinformatics studies and toxicity risk assessments, it can be concluded that the active compounds in pistachio peel may be beneficial as a safe antioxidant and therapeutic agent for cancer. However, further in vivo and in vitro studies are required to substantiate these findings.

کلیدواژه ها:

Breast Cancer ، TLR۴ ، STAT۳ ، Pistachio Peel