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

Zijian Han; Jintian Li; Qingyi Liao; Ruitong Luo; Leyun Wu; Yulong Shi; Liping Zhou; Qian Zhang; Máté Erdélyi; Weiliang Zhu; Zhijian Xu

doi:10.1021/acs.jmedchem.5c01043

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

J Med Chem. 2025 Jul 3. doi: 10.1021/acs.jmedchem.5c01043. Online ahead of print.

Authors

Zijian Han^{1

2}, Jintian Li^{1

2}, Qingyi Liao³, Ruitong Luo^{1

2}, Leyun Wu^{1

2}, Yulong Shi^{1

2}, Liping Zhou^{1

2}, Qian Zhang⁴, Máté Erdélyi⁵, Weiliang Zhu^{1

2

3}, Zhijian Xu^{1

2

3}

Affiliations

¹ State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
² School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
³ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, China.
⁴ School of Computer Science and Technology, Shanghai Frontiers Science Center of Molecule Intelligent Syntheses, East China Normal University, Shanghai 200241, China.
⁵ Department of Chemistry - BMC, Uppsala University, 751 23 Uppsala, Sweden.

PMID: 40607888
DOI: 10.1021/acs.jmedchem.5c01043

Abstract

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.