title: Inhibition of the Cysteine Protease Human Cathepsin L by Triazine Nitriles: Amide⋅⋅⋅Heteroarene π-Stacking Interactions and Chalcogen Bonding in the S3 Pocket.
abstract: 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 (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-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.
authors.affiliation: Laboratorium für Organische Chemie, ETH Zurich, Vladimir-Prelog-Weg 3, 8093, Zurich, Switzerland.
authors.forename: Maude
authors.initials: M
authors.lastname: Giroud
authors.affiliation: Laboratorium für Organische Chemie, ETH Zurich, Vladimir-Prelog-Weg 3, 8093, Zurich, Switzerland.
authors.forename: Jakov
authors.initials: J
authors.lastname: Ivkovic
authors.affiliation: Laboratorium für Organische Chemie, ETH Zurich, Vladimir-Prelog-Weg 3, 8093, Zurich, Switzerland.
authors.forename: Mara
authors.initials: M
authors.lastname: Martignoni
authors.affiliation: Laboratorium für Organische Chemie, ETH Zurich, Vladimir-Prelog-Weg 3, 8093, Zurich, Switzerland.
authors.forename: Marianne
authors.initials: M
authors.lastname: Fleuti
authors.affiliation: Laboratorium für Organische Chemie, ETH Zurich, Vladimir-Prelog-Weg 3, 8093, Zurich, Switzerland.
authors.forename: Nils
authors.initials: N
authors.lastname: Trapp
authors.affiliation: F. Hoffmann-La Roche Ltd., Pharma Research and Early Development (pRED), Therapeutic Modalities, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Haap
authors.affiliation: F. Hoffmann-La Roche Ltd., Pharma Research and Early Development (pRED), Therapeutic Modalities, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kuglstatter
authors.affiliation: F. Hoffmann-La Roche Ltd., Pharma Research and Early Development (pRED), Therapeutic Modalities, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
authors.forename: Jörg
authors.initials: J
authors.lastname: Benz
authors.affiliation: F. Hoffmann-La Roche Ltd., Pharma Research and Early Development (pRED), Therapeutic Modalities, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
authors.forename: Bernd
authors.initials: B
authors.lastname: Kuhn
authors.affiliation: Institut für Pharmazie und Biochemie, Johannes Gutenberg-Universität Mainz, Staudinger Weg 5, 55128, Mainz, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Schirmeister
authors.affiliation: Laboratorium für Organische Chemie, ETH Zurich, Vladimir-Prelog-Weg 3, 8093, Zurich, Switzerland.
authors.forename: François
authors.initials: F
authors.lastname: Diederich
mesh_terms: D000577:Amides / Q000737:chemistry; D001665:Binding Sites; D056668:Cathepsin L / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018011:Chalcogens / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011789:Quantum Theory; D014227:Triazines / Q000737:chemistry*
chemical_list: D000577:Amides; D018011:Chalcogens; D008024:Ligands; D009570:Nitriles; D014227:Triazines; D056668:Cathepsin L
keywords: chalcogen bonding; conformational analysis; cysteine proteases; heteroarene scan; peptide amide bonds; π-stacking