5mae

Publication Abstract from PubMed

We report an extensive "heteroarene scan" of triazine nitrile ligands of the cysteine protease human cathepsin L (hCatL) to investigate pi-stacking on the peptide amide bond Gly67-Gly68 at the entrance of the S3 pocket. This heteroarenepeptide bond stacking was supported by a co-crystal structure of an imidazopyridine ligand with hCatL. Inhibitory constants (Ki ) are strongly influenced by the diverse nature of the heterocycles and specific interactions with the local environment of the S3 pocket. Binding affinities vary by three orders of magnitude. All heteroaromatic ligands feature enhanced binding by comparison with hydrocarbon analogues. Predicted energetic contributions from the orientation of the local dipole moments of heteroarene and peptide bond could not be confirmed. Binding of benzothienyl (Ki =4 nm) and benzothiazolyl (Ki =17 nm) ligands was enhanced by intermolecular C-SO=C interactions (chalcogen bonding) with the backbone C=O of Asn66 in the S3 pocket. The ligands were also tested for the related enzyme rhodesain.

Inhibition of the Cysteine Protease Human Cathepsin L by Triazine Nitriles: AmideHeteroarene pi-Stacking Interactions and Chalcogen Bonding in the S3 Pocket.,Giroud M, Ivkovic J, Martignoni M, Fleuti M, Trapp N, Haap W, Kuglstatter A, Benz J, Kuhn B, Schirmeister T, Diederich F ChemMedChem. 2016 Dec 19. doi: 10.1002/cmdc.201600563. PMID:27992115^[1]

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