**1. Introduction**

Fluorine is the most electronegative element, and this property has a significant impact on the bioavailability, lipophilicity, metabolic stability, acidity/basicity, and toxicity [1]. Since the second half of the 20th century [2], researchers have been exploring the possibility of using fluorinated molecules in medicine [1,3]. The important position of fluorinated molecules in medicinal chemistry can be understood by the exceptionally large number of fluorine-containing drugs currently available on the pharmaceutical market (Figure 1). The share of fluorinated compounds rose from 2% in 1970 to 8% in 1980, 13% in 1990, and reached 18% at the beginning of the 21st century. Among them, six products were in the "top-12" list and employed as anticancer, anti-inflammatory, analgesic, or antidepressant agents in medicine [4]. About 20% of the drugs used in 2010 contained fluorine atom(s) or fluoroalkyl group(s) [3], whereas in the last decade (2011–2020) 114 out of the 410 drugs approved by the Food and Drug Administration (FDA) (data from the Center for Drug Evaluation and Research (CDER)) [5] contained fluorine (Figure 1). Currently, fluorinated pharmaceuticals account for over 50% of the most profitable drugs (blockbuster drugs), and are also recognized as the best among the drugs used in almost all therapeutic areas [6].

The biological activity of drugs is determined by intermolecular interactions. These interactions also play an important role in stabilizing the ligand–biomolecule system. Hydrogen bonds (HBs), in particular, are considered to significantly influence the action of drug molecules on their targets [7–9]. Interestingly, fluorine or substituents containing this element have been shown to tune the intermolecular interactions in ligand–protein complexes [1,10]. Although characterized by high electronegativity, fluorine is a weak acceptor of HBs and, unlike other halogens, it is not a halogen bond (XB) donor in aromatic systems [11,12]. However, the results of our previous study on small model systems

**Citation:** Pietru´s, W.; Kafel, R.; Bojarski, A.J.; Kurczab, R. Hydrogen Bonds with Fluorine in Ligand– Protein Complexes-the PDB Analysis and Energy Calculations. *Molecules* **2022**, *27*, 1005. https://doi.org/ 10.3390/molecules27031005

Academic Editor: Miroslaw Jablonski

Received: 30 December 2021 Accepted: 29 January 2022 Published: 2 February 2022

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(e.g., 2,6-difluro-4-halogenoanilines) indicated that fluorine can act as a competitive and attractive acceptor for HBs and XBs as well as form F··· F interactions [13]. Additionally, it is considered that fluorine-containing HBs are not typical and do not behave like conventional HBs (e.g., O···H–O and N···H–N), as demonstrated by a more angular nature and preference for less electronegative donors [14].

**Figure 1.** Number of marketed drugs containing fluorine per decade. Data were collected from the DrugCentral 2021 database (accessed 30 April 2021).

The biological activity of compounds can be tuned with the use of fluorine. However, there are no rules of thumb for predicting the preferred fluorine substitution sites in a molecule. Despite numerous studies on fluorine, the influence of this element on the pharmacodynamics properties of drugs remains unclear. A statistical analysis of the nature, geometry, and frequency of interactions occurring between fluorine in small molecules and the biological targets included in the Protein Data Bank (PDB) repository may allow understanding of the role of fluorine in ligand–receptor (L–R) complexes. Therefore, we carried out a wide statistical analysis and calculations to quantitatively and qualitatively explore the HBs (contacts) formed with fluorine in biological systems. The findings of this study may contribute to a thorough understanding of the effects of fluorine, to enable its rational use in drug design and for improving the efficiency of computational methods [15,16].

## **2. Results and Discussion**
