So far, in addition to halogen atoms, other non-metallic atoms can become part of the aromatic heterocycle, and the target ring system is still aromatic.Lange, Andreas; Guenther, Marcel; Buettner, Felix Michael; Zimmermann, Markus O.; Heidrich, Johannes; Hennig, Susanne; Zahn, Stefan; Schall, Christoph; Sievers-Engler, Adrian; Ansideri, Francesco; Koch, Pierre; Laemmerhofer, Michael; Stehle, Thilo; Laufer, Stefan A.; Boeckler, Frank M. researched the compound: 3-(2,5-Dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole( cas:882562-40-5 ).SDS of cas: 882562-40-5.They published the article 《Targeting the Gatekeeper MET146 of C-Jun N-Terminal Kinase 3 Induces a Bivalent Halogen/Chalcogen Bond》 about this compound( cas:882562-40-5 ) in Journal of the American Chemical Society. Keywords: aminopyrimidine inhibitor halogen chalcogen bond methionine JNK3 crystal structure. We’ll tell you more about this compound (cas:882562-40-5).
We target the gatekeeper MET146 of c-Jun N-terminal kinase 3 (JNK3) to exemplify the applicability of X···S halogen bonds in mol. design using computational, synthetic, structural and biophys. techniques. In a designed series of aminopyrimidine-based inhibitors, we unexpectedly encounter a plateau of affinity. Compared to their QM-calculated interaction energies, particularly bromine and iodine fail to reach the full potential according to the size of their σ-hole. Instead, mutation of the gatekeeper residue into leucine, alanine, or threonine reveals that the heavier halides can significantly influence selectivity in the human kinome. Thus, we demonstrate that, although the choice of halogen may not always increase affinity, it can still be relevant for inducing selectivity. Determining the crystal structure of the iodine derivative in complex with JNK3 (4X21) reveals an unusual bivalent halogen/chalcogen bond donated by the ligand and the back-pocket residue MET115. Incipient repulsion from the too short halogen bond increases the flexibility of Cε of MET146, whereas the rest of the residue fails to adapt being fixed by the chalcogen bond. This effect can be useful to induce selectivity, as the necessary combination of methionine residues only occurs in 9.3% of human kinases, while methionine is the predominant gatekeeper (39%).
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Reference:
Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem