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PDBsum entry 4qh6
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Hydrolase/hydrolase inhibitor
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PDB id
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4qh6
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PDB id:
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| Name: |
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Hydrolase/hydrolase inhibitor
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Title:
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Crystal structure of cruzain with nitrile inhibitor n-(2-aminoethyl)- nalpha-benzoyl-l-phenylalaninamide
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Structure:
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Cruzipain. Chain: a, b, c, d, e. Synonym: cruzaine, major cysteine proteinase. Engineered: yes
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Source:
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Trypanosoma cruzi. Organism_taxid: 5693. Gene: cruzipain, genbank m84342.1. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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3.13Å
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R-factor:
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0.206
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R-free:
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0.244
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Authors:
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W.B.Fernandes,C.A.Montanari,J.H.Mckerrow
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Key ref:
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L.A.Avelar
et al.
(2015).
Molecular Design, Synthesis and Trypanocidal Activity of Dipeptidyl Nitriles as Cruzain Inhibitors.
Plos Negl Trop Dis,
9,
e0003916.
PubMed id:
DOI:
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Date:
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27-May-14
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Release date:
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05-Aug-15
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PROCHECK
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Headers
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References
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P25779
(CYSP_TRYCR) -
Cruzipain from Trypanosoma cruzi
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Seq:
Struc:
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467 a.a.
215 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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DOI no:
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Plos Negl Trop Dis
9:e0003916
(2015)
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PubMed id:
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Molecular Design, Synthesis and Trypanocidal Activity of Dipeptidyl Nitriles as Cruzain Inhibitors.
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L.A.Avelar,
C.D.Camilo,
S.de Albuquerque,
W.B.Fernandes,
C.Gonçalez,
P.W.Kenny,
A.Leitão,
J.H.McKerrow,
C.A.Montanari,
E.V.Orozco,
J.F.Ribeiro,
J.R.Rocha,
F.Rosini,
M.E.Saidel.
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ABSTRACT
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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.
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Links
