3N3G

4-(3-Trifluoromethylphenyl)-pyrimidine-2-carbonitrile as cathepsin S inhibitors: N3, not N1 is critically important

Summary for 3N3G

• Entry DOI: 10.2210/pdb3n3g/pdb
• Descriptor: Cathepsin S, DI(HYDROXYETHYL)ETHER, DIMETHYL SULFOXIDE, ... (8 entities in total)
• Functional Keywords: cathepsin s, covalent inhibitor, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Lysosome: P25774
• Total number of polymer chains: 2
• Total formula weight: 49695.70

Authors

Fradera, X.,Uitdehaag, J.C.M.,van Zeeland, M. (deposition date: 2010-05-20, release date: 2010-07-14, Last modification date: 2011-07-13)

Primary citation

Cai, J.,Fradera, X.,van Zeeland, M.,Dempster, M.,Cameron, K.S.,Bennett, D.J.,Robinson, J.,Popplestone, L.,Baugh, M.,Westwood, P.,Bruin, J.,Hamilton, W.,Kinghorn, E.,Long, C.,Uitdehaag, J.C.
4-(3-Trifluoromethylphenyl)-pyrimidine-2-carbonitrile as cathepsin S inhibitors: N3, not N1 is critically important.
Bioorg.Med.Chem.Lett., 20:4507-4510, 2010

PubMed Abstract: Using computer aided modelling studies, a new extended P2/S2 interaction was identified. This extended region can accommodate a variety of functional groups, such as aryls and basic amines. It was discovered that the N3 nitrogen of the pyrimidine-2-carbonitrile is critical for its cathepsin cysteine protease inhibition. N1 nitrogen also contributes to the inhibitory activity, but to a very limited degree. An 'in situ double activation' mechanism was proposed to explain these results.

PubMed: 20580231
DOI: 10.1016/j.bmcl.2010.06.043

Experimental method

X-RAY DIFFRACTION (1.6 Å)