Targeting TTK with Tinospora cordifolia phytochemicals for bone metastatic castration-resistant prostate cancer

Castration-resistant bone metastatic prostate cancer (CRBMPC) is the most dangerous variant of Prostate Cancer (PCa). Despite advancements in developing diverse therapeutic agents, an effective treatment for this perilous type of PCa remains elusive. This study aimed to identify a novel therapeutic target and a promising drug candidate from the Tinospora cordifolia stem phytochemicals, as they are well known for anti-inflammatory and anticancer activities. Microarray data were analyzed to identify Differentially Expressed Genes (DEGs) in cancer samples. The Protein-Protein Interaction (PPI) network was constructed and analyzed using Cytoscape. Gene ontology revealed functional enrichment of DEGs. Molecular docking revealed interactions between the protein and ligands. Drug-likeness evaluates pharmacokinetic properties. DFT analysis confirms the reactivity of the top compound. The MM-GBSA (Molecular Mechanics-Generalized Born Surface Area) binding free energy revealed a strong binding affinity for the top-docked complex. A 500 ns molecular dynamics simulation demonstrated the stability of the complex. MM-PBSA (Molecular Mechanics-Poisson-Boltzmann Surface Area) results showed residue-wise energy contribution. 685 up-regulated DEGs were found in the cancer samples. DEGs are involved in several biological processes. The network analysis identified Threonine Tyrosine Kinase (TTK) as a targetable protein. Tinosinen (-9.507 Kcal/mol) was found as the best docked phytochemical. MM-GBSA confirmed the strong binding affinity of the TTK-Tinosinen complex with a binding free energy of −58.04 Kcal/mol. Other studies confirm the stability of the TTK-Tinosinen complex. The current in-silico findings provide significant insights into prospective treatment approaches for CRBMPC and establish the groundwork for further experimental studies.