4QH6
Crystal structure of cruzain with nitrile inhibitor N-(2-AMINOETHYL)-NALPHA-BENZOYL-L-PHENYLALANINAMIDE
Summary for 4QH6
Entry DOI | 10.2210/pdb4qh6/pdb |
Descriptor | Cruzipain, N-(2-aminoethyl)-Nalpha-benzoyl-L-phenylalaninamide (2 entities in total) |
Functional Keywords | thiol protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
Biological source | Trypanosoma cruzi |
Total number of polymer chains | 5 |
Total formula weight | 113887.04 |
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 citation | Avelar, 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: 26173110DOI: 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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