5MAJ

CATHEPSIN L IN COMPLEX WITH 4-[cyclopentyl(imidazo[1,2-a]pyridin-2-ylmethyl)amino]-6-morpholino-1,3,5-triazine-2-carbonitrile

Summary for 5MAJ

• Entry DOI: 10.2210/pdb5maj/pdb
• Related: 5MAE
• Descriptor: Cathepsin L1, ~{N}-cyclopentyl-~{N}-(imidazo[1,2-a]pyridin-2-ylmethyl)-4-(iminomethyl)-6-morpholin-4-yl-1,3,5-triazin-2-amine, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: protease inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase
• Biological source: Homo sapiens (Human)
• Cellular location: Lysosome: P07711
• Total number of polymer chains: 1
• Total formula weight: 24660.25

Authors

Kuglstatter, A.,Stihle, M.,Benz, J. (deposition date: 2016-11-03, release date: 2017-01-11, Last modification date: 2024-10-16)

Primary citation

Giroud, M.,Ivkovic, J.,Martignoni, M.,Fleuti, M.,Trapp, N.,Haap, W.,Kuglstatter, A.,Benz, J.,Kuhn, B.,Schirmeister, T.,Diederich, F.
Inhibition of the Cysteine Protease Human Cathepsin L by Triazine Nitriles: AmideHeteroarene pi-Stacking Interactions and Chalcogen Bonding in the S3 Pocket.
ChemMedChem, 12:257-270, 2017

PubMed 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 (K ) 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 =4 nm) and benzothiazolyl (K =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.

PubMed: 27992115
DOI: 10.1002/cmdc.201600563

Experimental method

X-RAY DIFFRACTION (1 Å)