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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.


Markus Schade, Beatrix Merla, Bernhard Lesch, Markus Wagener, Simone Timmermanns, Katrien Pletinckx, Torsten Hertrampf. Highly Selective Sub-Nanomolar Cathepsin S Inhibitors by Merging Fragment Binders with Nitrile Inhibitors. Journal of medicinal chemistry. 2020 Oct 22;63(20):11801-11808

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PMID: 32880457

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