Potential role of glyceollin as anti-metastatic agent through transforming growth factor-β receptors inhibition signaling pathways: A computational study

Glyceollin is a phytoalexin compound derived from elicited soybean which has been proven as anti-metastatic agent through inhibition of Epithelial-Mesenchymal Transition (EMT) mechanism, but the overall mechanism remains unclear. Transforming Growth Factor-β (TGF-β) is one of the cytokines that can contribute in EMT by interacting with the TGF-β receptor (TGFBR). This study analyzed the potential of glyceollin which include glyceollin (Gln) I, II, III, and IV as TGFBR type I (TGFBR1) and II (TGFBR2) inhibitors to block signaling pathways for the EMT process. The results of binding affinity analysis through molecular docking revealed that Gln I had the potential role as TGFBR type I and II inhibitor with the smallest energy compared to other glyceollin isomers. Furthermore, Gln I had 14 and 6 interacted residues both hydrophobically and hydrogen bonded as well as a TGFBR1-inhibitor complex. Protein interaction analysis illustrated that TGFBR1 and TGFBR2 could interact with Smad-2, -3, -4, and Endoglin (ENG) which were involved in metastasis process through EMT mechanism. Augmentation of EMT regulator transcription factors activity could decrease E-cadherin expression and had implications for loss of cell-cell adhesion resulting in cancer metastasis. These data indicate that glyceollin I had a promising opportunity as an anti-metastasic compound through blockade of signaling pathways mediated by TGFBR. Further research is needed to validate glyceollin I inhibition activity in vitro against TGFBR.