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Halogen Bond in Medicinal Chemistry.

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Halogen Bond in Medicinal Chemistry
Halogen bond is driven by the σ-hole, a positively charged region on the hind side of chlorine (Cl),bromine (Br) and iodine (I) along the axis of R-Cl, R-Br and R-I bond that is caused by an anisotropyof electron density on the halogen. [1-2] Because of its presence in every amino acid, the backbone
C=O is the most prominent acceptor involved in halogen bonds as found from an analysis of PDB.
Additionally, halogen bonds can be formed involving protein residues, such as –OH in serine,threonine and tyrosine, -COOH in aspartate and glutamate, -SH in cysteine, -SMe in methionine, Nin histidine, and pi-surface of phenylalanine, tyrosine and tryptophan (Figure 11). Therefore, thismultitude of different interactions possibilities in ligand-protein interactions makes halogen bond avery useful tool to enhance affinity and selectivity.

Figure 11. σ-Hole of Cl, Br and I; Different types of halogen bonds in ligand-protein interactions.

It was interesting to observe that a single chlorine in compound 33 increased potency by > 5-foldcomparing with analog compound 32. The same trend was also observed when comparing
compound 34 and compound 35 with 20-fold difference in potency caused by a single chlorine. [3]To better understand this observation and further optimize, an X-ray crystal structure of compound
33 bound to HPK1 was obtained. The chlorine atom at the C2 position on compound 33 forms ahalogen bond with the gatekeeper Met91, well explaining the reason for potency difference causedby chlorine atoms in compound 33 and compound 35.

Figure 12. Halogen bond between chlorine and sulfur of Met91 increased potency. (PDB code: 8FH4)

Fragment-based drug discovery (FBDD) has become a standard asset in the search for structurally
novel small-molecule therapeutics. Incorporation of halogens into fragments could change theirinteraction profile significantly based on halogen bond, leading to previously overlooked binding
modes to known targets, which could have intrinsic advantages in selectivity. [4] Screening DYRK1aagainst a halogen-enriched fragment library using an STD-NMR protocol generated fragment hit 36,2

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with Kd = 533 uM and a high LE = 0.45. The crystal structure of DYRK1a in complex with fragment 36
was solved. The binding mode in the ATP pocket is dominated by a halogen bond between Br andthe backbone C=O of E239 (Figure 13). Structure-activity relationship (SAR) insights gained fromanalogues demonstrated that: 1) removing a nitrogen from triazole increased affinity by > 10-fold(36 vs 37); 2) the pyridine nitrogen seems to have no significant effect (37 vs 38). A new fragmentgrowth vector was established, and incorporation of an acetamide increased the affinity to singledigit 4 uM.

Figure 13. Br of compound 36 forms a halogen bond with the backbone C=O of E239. (PDB code: 7ZH8)

The general trend for the strength order of halogen bond is Cl < Br < I. As exemplified in Figure 14,
halogen bond between chlorine in compound 41 and the backbone C=O of Phe217 brought 25-foldincreased affinity (40 vs 41). The affinity trend from compound 41 to 43 is consistent with thestrength order of halogen bond, although the difference is within 4-fold. [5]Figure 14. Br of compound 42 forms a halogen bond with the backbone C=O of Phe217.

With possibility of improving the bioactivity by halogen bond in mind, hydrogen atom in compound
44 was replaced by halogen atoms: Cl in compound 45, Br in compound 46 and I in compound 47(Figure 15). [6] The affinity trend from compound 45 to 47 is also consistent with the strength orderof halogen bond. X-ray crystal structures of compound 45 and compound 46 bound to PDE5 wereobtained. Both Cl in compound 45 and Br in compound 46 form halogen bonds with O of PDE5residue Y612, which agrees with observation in affinity increasing.

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Innovative chemistry for a better futureFigure 15. Halogen bonds between Cl or Br and O of PDE5 residue Y612.

References[1] Rainer Wilcken; et al. Principles and applications of halogen bonding in medicinal chemistry andchemical biology. J. Med. Chem. 2013, 56, 1363-1388.
[2] Nicolas K. Shinada; et al. Halogens in protein-ligand binding mechanism: a structural
perspectivel. J. Med. Chem. 2019, 62, 9341-9356.
[3] Rebecca A. Gallego; et al. Design and synthesis of functionally active 5-amino-6-aryl
pyrrolopyrimidine inhibitors of hematopoietic progenitor kinase 1. J. Med. Chem. 2019, 62,doi:10.1021/acs.jmedchem.2c02038.
[4] Marcel Dammann; et al. Screening of a halogen-enriched fragment library leads tounconventional binding modes. J. Med. Chem. 2022, 65, 14539-14552.
[5] Yu Zhou; et al. Exploring halogen bonds in 5-hydroxytryptamine 2B receptor-ligand interactions.
ACS Med. Chem. Lett. 2018, 9, 1019-1024.
[6] Zhijian Xu; et al. Utilization of halogen bond in lead optimization: a case study of rational designof potent phosphodiesterase type 5 (PDE5) inhibitors. J. Med. Chem. 2011, 54, 5607-5611.

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