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

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”.

Isomeric Activity Cliffs—A Case Study for Fluorine Substitution of Aminergic G Protein-Coupled Receptor Ligands

“…Notably, the introduction of fluorine to bioactive compounds can lead to either an improvement or a deterioration of biological activity [ 4 , 7 , 16 , 17 ]. However, rules of thumb for fluorination to obtain highly potent compounds have not been defined thus far.…”

“…The ΔΔG values resulting from our workflow closely correlated with biological data (ΔpK i ) ( Figure 3 ), which also suggests that fluorine does not create its own stabilizing effects. However, the induced effects are an important factor influencing the potency change [ 7 ].…”

“…The ∆∆G values resulting from our workflow closely correlated with biological data (∆pK i ) (Figure 3), which also suggests that fluorine does not create its own stabilizing effects. However, the induced effects are an important factor influencing the potency change [7]. The next F i SAR example (Figure 4) illustrates the 5-HT2a ligands with a difference in the phenethanone piperazine linker or phenethylpiperazine linker [20].…”

“…Fluorine-containing compounds constitute over 50% of blockbuster drugs [ 6 ], e.g., (aggregated sales for 2021) Biktarvy (USD 8.624 Billion), Trikafta (USD 5.697 Billion), Xtandi (USD 5.636 Billion) and Invega (USD 4.022 Billion). In the last decade (2011–2020), fluorinated drugs constituted 30% of all compounds approved by the Food and Drug Administration (FDA) [ 7 ]. Additionally, fluorinated drug candidates that enter clinical trials are frequently observed (called emerging drugs), e.g., GS-6207 (lenacapavir—III phase, HIV-1) [ 8 ], AZD-9833 (camizestrant—III phase, breast cancer) [ 9 ] or BI-425809 (iclepertin—III phase, schizophrenia) [ 10 ].…”

Hydrogen Bonds

“…Based on data from both the Protein Data Bank and theoretical calculations, Pietruś, Kafel, Bojarski, and Kurczab detail the results of their research on the abundance, structure, and strength of the hydrogen bond with the fluorine atom as an acceptor [ 4 ]. The authors confirm that fluorine is a weak proton acceptor and thus forms weak hydrogen bonds; these are rather forced by the presence of stronger ligand–receptor interactions.…”