Hybrid Molecules Containing Methotrexate, Vitamin D, and Platinum Derivatives: Synthesis, Characterization, In VitroCytotoxicity, In Silico ADME Docking, Molecular Docking and Dynamics

Abstract Designing hybrid‐based drugs is one promising strategy for developing effective anticancer drugs that explore combination therapy to enhance treatment efficacy, overcome the development of drug resistance, and lower treatment duration. Bisphosphonates and Vitamin D are commonly administered drugs for the treatment of bone diseases and the prevention of bone metastases. Platinum‐based and methotrexate are widely used anticancer drugs in clinics. However, their use is hampered by adverse side effects. Hybrid‐based compounds containing either bisphosphonate, vitamin D, platinum‐based, or methotrexate were synthesized and characterized using FTIR, 1 H‐, 31 P, 13 C‐NMR, and UHPLC‐HRMS which confirmed their successful synthesis. The hydroxyapatite bone binding assay revealed a promising percentage binding affinity of the bisphosphonate hybrid compounds. In vitro cytotoxicity assays on MCF‐7 and HT‐29 cell lines revealed a promising cytotoxic effect of hybrid 19 at 50 and 100 μg/mL on HT‐29 and hybrid 15 on MCF‐7 at 100 μg/mL. Molecular docking and dynamics simulation analysis revealed a binding affinity of −9.70 kcal/mol for hybrid 15 against Human 3 alpha‐hydroxysteroid dehydrogenase type 3, showing its capability to inhibit Human 3 alpha‐hydroxysteroid dehydrogenase type 3. The Swiss ADME, ProTox‐II, GUSAR (General Unrestricted Structure‐Activity Relationships), and molecular docking and dynamics studies revealed that these compounds are promising anticancer compounds.