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Publication Abstract from PubMed

Compared to aryl-aryl pi-stacking interactions, the analogous stacking of heteroarenes on amide pi systems is less well understood and vastly underutilized in structure-based drug design. Recent theoretical studies have delineated the important geometric coordinates of the interaction, some of which have been confirmed with synthetic model systems based on Rebek imides. Unfortunately, a broadly useful and tractable protein-ligand model system of this interaction has remained elusive. Here we employed a known inhibitor scaffold to study pi-stacking of diverse heteroarene substituents on the amide face of Gly238 in the cephalosporinases CTX-M-14 and CTX-M-27. Biochemical inhibition constants (K i) and biophysical binding constants (K d) were determined for nineteen new analogues against both enzymes, while multiple high-resolution co-crystal structures revealed remarkably consistent placement of the probe heteroarene on Gly238. The data presented support the predicted importance of opposing dipoles in amide-heteroarene interactions and should be useful for evaluating other theoretical predictions concerning these interactions.

An Empirical Study of Amide-Heteroarene pi-Stacking Interactions Using Reversible Inhibitors of a Bacterial Serine Hydrolase.,DeFrees K, Kemp MT, ElHilali-Pollard X, Zhang X, Mohamed A, Chen Y, Renslo AR Org Chem Front. 2019 Jun 7;6(11):1749-1756. doi: 10.1039/c9qo00342h. Epub 2019, May 15. PMID:32774871^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.