Hydrogen Bond-Induced Binding between Organofluorine and Protein via Fluorine Atoms: A Database Survey and Quantum Chemistry Calculation Study

Fluorination is common in drug design and may significantly enhance bioactivity, although the underlying mechanism is not elucidated. We noticed a coexisting interaction pattern, viz., F···H and F···O/N/S interactions between organofluorines and protein binding pockets via fluorine atoms. Through database analysis and quantum chemistry calculations, we revealed a hydrogen bond-induced fluorine bond (HBiFB), involving a pseudopocket formed by hydrogen bond donors and halogen bond acceptors. HBiFBs show interaction energies of −1.5 to −4.0 kcal/mol and consistently enhance ligand–protein interactions by ∼1 kcal/mol. Moreover, HBiFB possesses a positively charged σ-hole, bond critical points, intermolecular electron transfer, and intramolecular electron redistribution. These findings highlight HBiFB as a potentially generalizable noncovalent force in fluorinated drug optimization.