Effect of Halogen Substitution on Benzimidazole Binding to DHFR.

This project investigates how halogen substitution (F, Cl, Br, I) affects the binding of benzimidazole derivatives to the DHFR (Dihydrofolate Reductase) enzyme using molecular docking. The DHFR structure (PDB ID: 1U72) was prepared by removing extra chains and minimizing the protein. Ligands were designed in ChemDraw, optimized using Gaussian, and docked with AutoDock Vina through PyRx. Binding poses and interactions were analyzed in Discovery Studio. The results show that all derivatives retain the core Val115 hydrogen bond and π–π stacking with Phe34, while halogen substitution influences hydrophobic interactions and overall pocket complementarity. Fluorine enhances polarity and hydrogen bonding, whereas Cl, Br, and I mainly increase hydrophobic and dispersion stabilisation. The comparison provides a clear structure–activity relationship for halogenated benzimidazole scaffolds targeting DHFR.