*Article* **Hydrogen Bonds with Fluorine in Ligand–Protein Complexes-the PDB Analysis and Energy Calculations**

**Wojciech Pietru´s, Rafał Kafel, Andrzej J. Bojarski and Rafał Kurczab \***

Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Krakow, Poland; pietrus@if-pan.krakow.pl (W.P.); rafal.kafel@gmail.com (R.K.);

bojarski@if-pan.krakow.pl (A.J.B.)

**\*** Correspondence: kurczab@if-pan.krakow.pl; Tel.: +48-126-62-3301

**Abstract:** Fluorine is a common substituent in medicinal chemistry and is found in up to 50% of the most profitable drugs. In this study, a statistical analysis of the nature, geometry, and frequency of hydrogen bonds (HBs) formed between the aromatic and aliphatic C–F groups of small molecules and biological targets found in the Protein Data Bank (PDB) repository was presented. Interaction energies were calculated for those complexes using three different approaches. The obtained results indicated that the interaction energy of F-containing HBs is determined by the donor–acceptor distance and not by the angles. Moreover, no significant relationship between the energies of HBs with fluorine and the donor type was found, implying that fluorine is a weak HB acceptor for all types of HB donors. However, the statistical analysis of the PDB repository revealed that the most populated geometric parameters of HBs did not match the calculated energetic optima. In a nutshell, HBs containing fluorine are forced to form due to the stronger ligand–receptor neighboring interactions, which make fluorine the "donor's last resort".

**Keywords:** fluorine; PDB; hydrogen bonds; HBs
