3IEJ

Pyrazole-based Cathepsin S Inhibitors with Arylalkynes as P1 Binding Elements

Summary for 3IEJ

Entry DOI	10.2210/pdb3iej/pdb
Descriptor	Cathepsin S, 2-[3-{4-chloro-3-[(4-chlorophenyl)ethynyl]phenyl}-1-(3-morpholin-4-ylpropyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]-2-oxoethanol (3 entities in total)
Functional Keywords	cathepsin s, disulfide bond, glycoprotein, hydrolase, lysosome, polymorphism, protease, thiol protease, zymogen
Biological source	Homo sapiens (human)
Cellular location	Lysosome: P25774
Total number of polymer chains	2
Total formula weight	49969.69
Authors	Bembenek, S. (deposition date: 2009-07-22, release date: 2009-10-06, Last modification date: 2024-11-27)
Primary citation	Ameriks, M.K.,Axe, F.U.,Bembenek, S.D.,Edwards, J.P.,Gu, Y.,Karlsson, L.,Randal, M.,Sun, S.,Thurmond, R.L.,Zhu, J. Pyrazole-based cathepsin S inhibitors with arylalkynes as P1 binding elements. Bioorg.Med.Chem.Lett., 19:6131-6134, 2009 Cited by PubMed Abstract: A crystal structure of 1 bound to a Cys25Ser mutant of cathepsin S helped to elucidate the binding mode of a previously disclosed series of pyrazole-based CatS inhibitors and facilitated the design of a new class of arylalkyne analogs. Optimization of the alkyne and tetrahydropyridine portions of the pharmacophore provided potent CatS inhibitors (IC50=40-300 nM), and an X-ray structure of 32 revealed that the arylalkyne moiety binds in the S1 pocket of the enzyme. PubMed: 19773165 DOI: 10.1016/j.bmcl.2009.09.014 PDB entries with the same primary citation
Experimental method	X-RAY DIFFRACTION (2.18 Å)

Structure validation