Targeting ABCB1 and ABCG2 transporters to combat cancer stem cell-mediated drug resistance and relapse: an integrated...

Cancer relapse commonly occurs in patients after completion of chemotherapy treatment, and CSCs are responsible for chemo resistance. Which is done by multiple mechanisms, among them one of the major contributors being the overexpression of ABC family receptors namely ABCB1(P-Gp), ABCG2(BCRP) and ABCC1(MRP1) on the plasma membrane. Modulating the activity of these receptors may reduce therapy resistance. In this article, we retrieved plant derived bioactive compounds from NPACT databases that were subjected to molecular docking, Molecular dynamic simulation, and MMGBSA analysis against ABCB1 and ABCG2 transporters. Docking precision scores of Crocetin, Gartanin and sulfuretin were - 7.36, -5.214 and - 5.196 kcal/mol respectively, which was more negative than standard reference modulator zosuquidar (-2.238 kcal/mol) in ABCB1. Docking precision Score of catechin, Garcinone C and taxifolin were - 7.36, -7.009, -6.895 kcal/mol, which was more negative than standard reference modulator imatinib (-0.936 kcal/mol) in ABCG2. RMSD (root mean square deviation) and RMSF (root mean square fluctuation) graphs of Molecular dynamic simulation study indicates that Crocetin, Gartanin and sulfuretin exhibit stronger and stable binding affinity with ABCB1 and Catechin, Garcinone C and Taxifolin demonstrate stable interaction and binding affinity with ABCG2 than respective reference modulators. The binding free energy (ΔGbind) of Crocetin, Gartanin and sulfuretin were - 35.6863, -38.0847 and - 31.4192 kcal/mol respectively and reference modulator zosuquidar was - 30.7985 kcal/mol with ABCB1 transporter protein. In case of ABCG2 the binding free energy (ΔGbind) of catechin, Garcinone C and taxifolin were - 36.3694, -67.2987, -60.6426 kcal/mol respectively and reference modulator Imatinib was - 35.355 kcal/mol. Integrated molecular docking and MMGBSA analyses confirmed that the identified compounds display superior binding affinity and energetically stable interactions with respective targets and ABCG2 and may have possessive ABCB1 modulatory effect.

The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00776-4.