Integrative computational repositioning of Foretinib and PF-03715455 as potential GSTP1 inhibitors for cancer chemosensitization

Glutathione S-transferase P1 (GSTP1) plays a key role in tumor progression and drug detoxification, making it a promising target for reversing chemoresistance in cancer cells. Although several GSTP1 inhibitors have been identified, none have progressed to clinical use, mainly because of low specificity and adverse effects. In this work, we used a virtual screening approach that integrates molecular docking and QSAR modeling to identify, through consensus, new GSTP1 inhibitors among approved and experimental compounds listed in the DrugBank database. PF-03715455 and Foretinib emerged as the most promising candidates among the top-ranked compounds, based on docking scores, predicted pIC₅₀ values, and binding free-energy analysis. Molecular dynamics (MD) simulations confirmed that both compounds maintained stable binding conformations and exhibited strong affinity for GSTP1, outperforming the reference inhibitor, TER117. This study presents a novel use of PF-03715455 and reveals a new mechanism for Foretinib, which stabilizes the dynamics essential for GSTP1 function and may prevent substrates from binding to the two active sites, H and G, thereby exerting potent inhibitory effects similar to those of reference inhibitors. This repositioning strategy could reduce costs and accelerate the discovery and development of GSTP1 inhibitors, paving the way for clinical use to improve chemosensitivity in cancer.