Importance of R-CF3•••O Tetrel Bonding Interactions in Biological Systems

In this article, ab initio calculations have been combined with a search in the Protein Data Bank (PDB) to demonstrate the importance of a-hole tetrel bonding interactions in biological systems. In particular, we focus our attention on the ability of the -CF3 group to participate in noncovalent interactions as Lewis acids, and we show the importance of this interaction in the inhibition mechanism of a NADP+-dependent isocitrate dehydrogenase (IDH) enzyme that converts isocitrate to a-ketoglutarate. IDH mutations are found in multiple hematologic and solid tumors, inducing premalignant disorders. A potent triazine-based inhibitor of the mutant IDH (enasidenib) presents two, -CF3, groups in the structure. One establishes a tetrel bonding interaction with an aspartate residue that contributes, to the binding and selectivity of the inhibitor to the active site.