Computational repurposing of Trimethoprim: molecular docking and molecular dynamics simulation studies suggest a potential inhibition of colchicine-binding site.

Abstract Cancer is a major global health concern, and its incidence is projected to rise in the coming years. Drug repurposing, the identification of new uses for existing drugs, offers a promising approach to accelerating the development of potent and less toxic anti-cancer agents. This in silico study explored the possible repurposing of trimethoprim, an approved synthetic antimicrobial, as a colchicine-binding site (CBS) inhibitor using molecular docking and molecular dynamics (MD) simulations. Trimethoprim shares structural similarities and pharmacophoric features with colchicine and the combretastatins, potent antimitotic agents that target the CBS. The docking results showed that trimethoprim achieved a good binding affinity to the CBS, with an average CDOCKER_ENERGY of -33.75 kcal/mol. The MD simulations (100 nanoseconds) confirmed the stability of the trimethoprim-tubulin complex, with a root mean square deviation (RMSD) of less than 2.5 Å for the protein backbone. The root mean square fluctuation (RMSF) of the binding site residues increased, indicating their increased flexibility. The radius of gyration (Rg) also increased within acceptable limits, suggesting that the protein unfolds to accommodate trimethoprim binding. The binding energy calculated using the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) approach was − 27.3 kcal/mol, which further confirms the docking results. Overall, the findings of this study provide preliminary evidence that trimethoprim has the potential to be repurposed as a CBS inhibitor. Further in vitro and in vivo studies are needed to validate its efficacy and safety as a potential anti-cancer agent.