CF2X moieties can be used as unconventional halogen bond donors drug discovery. They provide completely new opportunities to harness highly directional XB interactions. The CF2X structural motif is underrepresented in drug discovery and has hardly been applied so far, making it a promising area for exploration.
Vaas et al. propose that unconventional or unique binding modes could be explored based on CF2X-containing libraries, allowing for the discovery of unclaimed, patentable chemotypes and the establishment of added therapeutic opportunities. Their work also demonstrates that molecules containing C(sp3)F2X moieties attached by linker systems such as ethers or amides are synthetically accessible and that amide derivatives are particularly suitable for fragment-based drug discovery.
As an example, fragment 23 features an XB of CF2Br toward the P-loop, as well as chalcogen bonds, which are unique molecular interaction features. The implementation of CF2X acetamides into HEFLibs and biophysical evaluation (STD-NMR/ITC), followed by X-ray analysis, revealed these features and provided insights into the binding mode and interaction geometry of the fragment with the protein. This information can be used to design and optimize small molecules that target JNK3 and potentially other proteins with similar binding sites.
PDB structure still to be released: https://lnkd.in/eES9pMJj
CF2X = X = Cl, Br, or I
JNK3 = c-Jun N-terminal kinase 3