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.

Combination of bendamustine-azacitidine against Syk target of breast cancer: an in silico study.

Breast cancer (BC) is the most serious and second leading cause of death in women worldwide. When breast cancer is diagnosed and treated early, the chance of long-term survival is up to 90%. On the other hand, 90% of BC patient deaths are due to metastasis and a lack of effective early diagnosis. The existing conventional chemotherapy provides negative feedback due to transportation barriers towards the action sites, multidrug resistance, poor bio-availability, non-specific delivery and systemic side effects on the healthy tissue. Syk protein Kinase has been reported in BC, as a tumor modulator, providing a pro-survival signal and also by restricting epithelial-mesenchymal transition, enhancing cell-cell interactions and inhibiting migration. In the present study, we explored the possibility of targeting BC by attenuating Syk protein Kinase. Hence, we have conjugated the hydrophobic Bendamustine (BEN) and hydrophilic Azacitidine (AZA) anticancer drugs to evaluate their efficacy against BC. The native drugs (BEN and AZA) and designed drug-drug conjugate (BEN-AZA) were docked with Syk protein. Then, the docked complex was performed for Binding Free Energy and Molecular Dynamics Simulations. Furthermore, DFT and ADME properties were carried out. The results revealed that the designed drug-drug conjugate has a better docking score, ΔGbind and admirable stability throughout the simulation when compared with native drugs. In DFT and ADME analyses, the designed drug-drug conjugate has shown good stereo electronic features and pharmaceutical relevant parameters than that of native drugs. The overall results suggested that the designed drug-drug conjugate may be a suitable candidate for BC treatment.Communicated by Ramaswamy H. Sarma.