Designing a novel drug–drug conjugate as a prodrug for breast cancer therapy: in silico insights

Breast cancer (BC) poses a significant global health threat, necessitating innovative therapeutic approaches. The ribosomal s6 kinase 2 (RSK2) has emerged as a promising target due to its roles in cell proliferation and survival. This study proposes a drug–drug conjugate prodrug comprising Methotrexate (hydrophobic) and Capecitabine (hydrophilic) for BC treatment. In silico approaches, including Molecular Docking, Molecular Dynamics Simulations, MM-PBSA, ADME, and DFT calculations were employed to evaluate the prodrug’s potential. The designed MET-CAP ligand exhibits a robust docking score (−8.980 kcal/mol), superior binding affinity (−53.16 kcal/mol), and stable dynamic behavior (0.62 nm) compared to native ligands. The DFT results reveal intramolecular charge transfer in MET-CAP (HLG = 0.09 eV), indicating its potential as a BC inhibitor. ADME analysis suggests satisfactory pharmaceutically relevant properties. The results indicate that the conjugated MET-CAP ligand exhibits favorable binding characteristics, stability, and pharmaceutically relevant properties, making it a potential RSK2 inhibitor for BC therapy. The multifaceted approach provides insights into binding interactions, stability, and pharmacokinetic properties, laying the foundation for further experimental validation and potential clinical development.