Premium
Inhibition of the Cysteine Protease Human Cathepsin L by Triazine Nitriles: Amide⋅⋅⋅Heteroarene π‐Stacking Interactions and Chalcogen Bonding in the S3 Pocket
Author(s) -
Giroud Maude,
Ivkovic Jakov,
Martigi Mara,
Fleuti Marianne,
Trapp Nils,
Haap Wolfgang,
Kuglstatter Andreas,
Benz Jörg,
Kuhn Bernd,
Schirmeister Tanja,
Diederich François
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600563
Subject(s) - chemistry , stereochemistry , peptide bond , amide , peptide , hydrogen bond , organic chemistry , molecule , biochemistry
We report an extensive “heteroarene scan” of triazine nitrile ligands of the cysteine protease human cathepsin L (hCatL) to investigate π‐stacking on the peptide amide bond Gly67–Gly68 at the entrance of the S3 pocket. This heteroarene⋅⋅⋅peptide bond stacking was supported by a co‐crystal structure of an imidazopyridine ligand with hCatL. Inhibitory constants ( K i ) 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 ( K i =4 n m ) and benzothiazolyl ( K i =17 n m ) ligands was enhanced by intermolecular C−S⋅⋅⋅O=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.