Inhibition of the Cysteine Protease Human CathepsinL by Triazine Nitriles: AmideHeteroarene pi -Stacking Interactions and Chalcogen Bonding in the S3 Pocket

• Published in: ChemMedChem 2017-02, Vol.12 (3), p.257-270
• Main Authors: Giroud, Maude, Ivkovic, Jakov, Martignoni, Mara, Fleuti, Marianne, Trapp, Nils, Haap, Wolfgang, Kuglstatter, Andreas, Benz, Jorg, Kuhn, Bernd, Schirmeister, Tanja, Diederich, Francois
• Format: Article
• Language: ger
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201600563

We report an extensive "heteroarene scan" of triazine nitrile ligands of the cysteine protease human cathepsinL (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 (K sub(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 sub(i)=4nm) and benzothiazolyl (K sub(i)=17nm) 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. Heteroarene scan: The introduction of heteroarene substituents in the S3 pocket of human cathepsinL (hCatL) enhances the binding affinity of triazine nitrile inhibitors over their corresponding aromatic hydrocarbon analogues. The heterocycles undergo pi -stacking on peptide amide bonds located at the entrance of the pocket. Inhibitory activities vary over three orders of magnitude in a series of ligands bearing bicyclic heteroarenes as S3 pocket vectors. Intermolecular chalcogen bonding is suggested to be responsible for the enhanced activity of sulfur-containing heterocycles. The insights into biomolecular recognition are supported by co-crystal structures, interaction network analysis, and conformational analyses.