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4QH6

Crystal structure of cruzain with nitrile inhibitor N-(2-AMINOETHYL)-NALPHA-BENZOYL-L-PHENYLALANINAMIDE

Summary for 4QH6
Entry DOI10.2210/pdb4qh6/pdb
DescriptorCruzipain, N-(2-aminoethyl)-Nalpha-benzoyl-L-phenylalaninamide (2 entities in total)
Functional Keywordsthiol protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
Biological sourceTrypanosoma cruzi
Total number of polymer chains5
Total formula weight113887.04
Authors
Fernandes, W.B.,Montanari, C.A.,McKerrow, J.H. (deposition date: 2014-05-27, release date: 2015-08-05, Last modification date: 2024-10-09)
Primary citationAvelar, L.A.,Camilo, C.D.,de Albuquerque, S.,Fernandes, W.B.,Goncalez, C.,Kenny, P.W.,Leitao, A.,McKerrow, J.H.,Montanari, C.A.,Orozco, E.V.,Ribeiro, J.F.,Rocha, J.R.,Rosini, F.,Saidel, M.E.
Molecular Design, Synthesis and Trypanocidal Activity of Dipeptidyl Nitriles as Cruzain Inhibitors.
Plos Negl Trop Dis, 9:e0003916-e0003916, 2015
Cited by
PubMed Abstract: A series of compounds based on the dipeptidyl nitrile scaffold were synthesized and assayed for their inhibitory activity against the T. cruzi cysteine protease cruzain. Structure activity relationships (SARs) were established using three, eleven and twelve variations respectively at the P1, P2 and P3 positions. A Ki value of 16 nM was observed for the most potent of these inhibitors which reflects a degree of non-additivity in the SAR. An X-ray crystal structure was determined for the ligand-protein complex for the structural prototype for the series. Twenty three inhibitors were also evaluated for their anti-trypanosomal effects and an EC50 value of 28 μM was observed for the most potent of these. Although there remains scope for further optimization, the knowledge gained from this study is also transferable to the design of cruzain inhibitors based on warheads other than nitrile as well as alternative scaffolds.
PubMed: 26173110
DOI: 10.1371/journal.pntd.0003916
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (3.13 Å)
Structure validation

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