6YYN

Structure of Cathepsin S in complex with Compound 14

This is a non-PDB format compatible entry.

Summary for 6YYN

• Entry DOI: 10.2210/pdb6yyn/pdb
• Descriptor: Cathepsin S, CITRATE ANION, ~{N}-methyl-3-[4-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperazin-1-yl]sulfonyl-propanamide, ... (5 entities in total)
• Functional Keywords: cathepsin s, inhibitor, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 51873.72

Authors

Wagener, M.,Schade, M.,Merla, B.,Hars, U.,Kueckelhaus, S.Q. (deposition date: 2020-05-05, release date: 2021-05-12, Last modification date: 2024-11-13)

Primary citation

Schade, M.,Merla, B.,Lesch, B.,Wagener, M.,Timmermanns, S.,Pletinckx, K.,Hertrampf, T.
Highly Selective Sub-Nanomolar Cathepsin S Inhibitors by Merging Fragment Binders with Nitrile Inhibitors.
J.Med.Chem., 63:11801-11808, 2020

PubMed Abstract: Pharmacological inhibition of cathepsin S (CatS) allows for a specific modulation of the adaptive immune system and many major diseases. Here, we used NMR fragment screening and crystal structure-aided merging to synthesize novel, highly selective CatS inhibitors with picomolar enzymatic Ki values and nanomolar functional activity in human Raji cells. Noncovalent fragment hits revealed binding hotspots, while the covalent inhibitor structure-activity relationship enabled efficient potency optimization.

PubMed: 32880457
DOI: 10.1021/acs.jmedchem.0c00949

Experimental method

X-RAY DIFFRACTION (2.22 Å)