Structural and energetic modulation of the raloxifene-STAT3 complex by metformin and cisplatin: implications for...

Raloxifene, a selective estrogen receptor modulator, has shown potential as an inhibitor of the STAT3 signaling pathway, which is frequently dysregulated in cancer and inflammatory diseases. In this study, molecular docking and molecular dynamics (MD) simulations were employed to evaluate the binding interaction between raloxifene and STAT3, and to assess how metformin and cisplatin may influence the stability of this interaction. Docking analysis revealed strong binding of raloxifene within the SH2 domain of STAT3, stabilized by hydrogen bonds and hydrophobic contacts with residues such as Glu638, Tyr640 and Trp623. MD simulations showed that the native raloxifene-STAT3 complex maintained high structural stability with RMSD values between 0.20-0.30 nm and an average radius of gyration (Rg) of ∼3.51 nm. In contrast, the presence of metformin led to increased RMSD, expanded Rg and higher solvent-accessible surface area, indicating structural destabilization. Cisplatin, on the other hand, stabilized the complex with lower RMSD, reduced Rg and decreased SASA. RMSF analysis revealed that key binding site residues such as Ser636 and Val637 exhibited higher fluctuations in the metformin system, whereas cisplatin decreased residue flexibility. Hydrogen bond autocorrelation showed more persistent interactions in the cisplatin-bound complex compared to metformin. MM-PBSA calculations supported these trends, with stronger binding energy observed for the native and cisplatin systems compared to the metformin-bound system. Overall, these findings suggest that while raloxifene forms a stable complex with STAT3, metformin disrupts this stability, whereas cisplatin enhances it, offering insights into potential drug-drug interactions and co-therapy design involving STAT3 inhibitors.