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.