Targeting P-glycoprotein-mediated drug resistance: in silico screening and in vitro evaluation of phytochemicals

Abstract Cancer remains one of the significant causes of mortality throughout the globe, with treatment often requiring prolonged therapy. Multidrug resistance, primarily mediated by P-glycoprotein (P-gp) transporters, poses a considerable challenge in the long-term treatment of cancer. To overcome this, P-gp inhibitors can be co-administered for improved drug accumulation and therapeutic efficacy. In the present study, a total of 37 phytochemicals were evaluated for their potential P-gp blocking activity using molecular docking and Molecular Mechanics/Generalized Born Surface Area analysis against the P-gp protein (PDB ID: 6FN1) and compared with Verapamil as a reference P-gp inhibitor. Among the screened compounds, Andrographolide demonstrated the most favourable binding interactions and was further subjected to molecular dynamics simulations, confirming its stable interaction with P-gp. Subsequent in vitro cell line studies revealed that Andrographolide, at effective inhibitory concentrations, did not exhibit inherent cytotoxicity but significantly enhanced the cell internalization and cytotoxicity of paclitaxel, a known P-gp substrate. This suggests that Andrographolide plays a role in reversing multidrug resistance through P-gp inhibition, rather than direct cell killing, for effective cancer therapy. These findings indicate that co-administration of phytochemicals, such as Andrographolide, may enhance cell internalization and the efficacy of anticancer drugs, thereby improving chemotherapy outcomes.