In Silico Evaluation of the Potential Inhibitory Effect of Deoxyelephantopin in Targeting GSTP1-Mediated Drug Resistance in Cancer Treatment: A Preliminary Study

Kılıç M., Sert M., Zeyrek C. T.

XI. Multidisciplinary Cancer Research Congress, İstanbul, Türkiye, 2 - 05 Temmuz 2026, ss.110, (Özet Bildiri)

  • Yayın Türü: Bildiri / Özet Bildiri
  • Basıldığı Şehir: İstanbul
  • Basıldığı Ülke: Türkiye
  • Sayfa Sayıları: ss.110
  • Ankara Üniversitesi Adresli: Evet

Özet

ABSTRACT

Introduction and Aim: Glutathione S-transferase Pi-1 (GSTP1) has been associated with resistance to both chemotherapy and radiotherapy. Ethacrynic acid (EA), a potent GSTP1 inhibitor, has limitations that restrict its clinical application. Deoxyelephantopin, a naturally occurring sesquiterpene lactone, has demonstrated anticancer activity in several experimental cancer models. However, its interaction with GSTP1 and its potential relevance to GSTP1-mediated drug resistance remain unclear. Therefore, this study aimed to evaluate the potential of deoxyelephantopin as a GSTP1 inhibitor candidate.

Materials and Methods: Deoxyelephantopin and the reference inhibitor EA were docked into the GSTP1 crystal structure (PDB ID: 2GSS). Ligand and protein preparation were performed using AutoDockTools, and docking simulations were carried out with AutoDock Vina. Binding affinities were expressed as ΔG (kcal/mol). The docking protocol was validated by re-docking the co-crystallized ligand, yielding RMSD values below 2Å.

Results: Deoxyelephantopin exhibited a stronger binding affinity toward GSTP1 (−7.8 kcal/mol) than EA (−6.2 kcal/mol). While EA formed four hydrogen bonds with ARG13, TYR7, and TYR108, deoxyelephantopin formed two hydrogen bonds with TYR108 and GLN51. The shared interaction with TYR108 suggests a similar binding region within the active site. In addition, hydrophobic interactions with ILE104, ARG13, and PHE8 may contribute to the stability of the deoxyelephantopin–GSTP1 complex. The observed binding orientation further indicates that the α,β-unsaturated lactone moiety of deoxyelephantopin may support Michael acceptor activity within the GSTP1/GSH system.

Discussion: Overall, these findings suggest that deoxyelephantopin interacts with a binding region similar to that of EA while exhibiting a higher binding affinity toward GSTP1. Its binding orientation and structural features further support a potential Michael acceptor role within the GSTP1/GSH system. Accordingly, deoxyelephantopin may warrant further investigation as a natural GSTP1 inhibitor for targeting GSTP1-mediated drug resistance. Experimental validation through in vitro and in vivo studies is required to confirm these computational findings.

Keywords: Deoxyelephantopin; Glutathione S-Transferase Pi-1 (GSTP1); Chemoresistance; Radioresistance; Sesquiterpene Lactone; Molecular Docking