【MedChem Spark】Halogen Bond in Medicinal Chemistry (Issue 4)
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By Jin Li
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 anisotropy of 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, N in histidine, and pi-surface of phenylalanine, tyrosine and tryptophan (Figure 1). Therefore, this multitude of different interaction possibilities in ligand-protein interactions makes halogen bond a very useful tool to enhance affinity and selectivity.
It was interesting to observe that a single chlorine in compound 33 increased potency by > 5-fold compared with analog compound 32. The same trend was also observed when comparing compound 34 and compound 35 with a 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 a halogen bond with the gatekeeper Met91, explaining the reason for the potency difference caused by chlorine atoms in compound 33 and compound 35.
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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 their interaction profile significantly based on halogen bond, leading to previously overlooked binding modes to known targets, which could have intrinsic advantages in selectivity. [4] Screening DYRK1a against a halogen-enriched fragment library using an STD-NMR protocol generated fragment hit 36, 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 and the backbone C=O of E239 (Figure 3). Structure-activity relationship (SAR) insights gained from analogs demonstrated that: 1) removing 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 fragment-growth vector was established, and the incorporation of an acetamide increased the affinity to single-digit 4 uM.
The general trend for the strength order of halogen bond is Cl < Br < I. As exemplified in Figure 4, the halogen bond between chlorine in compound 41 and the backbone C=O of Phe217 brought 25-fold increased affinity (40 vs 41). The affinity trend from compound 41 to 43 is consistent with the strength order of halogen bond, although the difference is within 4-fold. [5]
With the possibility of improving the bioactivity by halogen bond in mind, the hydrogen atom in compound 44 was replaced by halogen atoms: Cl in compound 45, Br in compound 46 and I in compound 47 (Figure 5). [6] The affinity trend from compound 45 to 47 is also consistent with the strength order of the halogen bond. X-ray crystal structures of compound 45 and compound 46 bound to PDE5 were obtained. Both Cl in compound 45 and Br in compound 46 form halogen bonds with O of PDE5 residue Y612, which agrees with the observation of affinity increasing.
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References
[1] Rainer Wilcken; et al. Principles and applications of halogen bonding in medicinal chemistry and chemical 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 to unconventional 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 design of potent phosphodiesterase type 5 (PDE5) inhibitors. J. Med. Chem. 2011, 54, 5607-5611.
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By Jin Li
Senior Director of PharmaBlock
Find out more at www.pharmablock.com