PDBsum entry 3kku

Hydrolase

PDB id: 3kku

Contents

Protein chain

215 a.a. *

Ligands

B95

EDO ×10

Z22

Waters ×310

* Residue conservation analysis

PDB id:

3kku

Name:

Hydrolase

Title:

Cruzain in complex with a non-covalent ligand

Structure:

Cruzipain. Chain: a. Synonym: cruzaine, major cysteine proteinase. Engineered: yes

Source:

Trypanosoma cruzi. Organism_taxid: 5693. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.28Å R-factor: 0.116 R-free: 0.144

Authors:

R.S.Ferreira,O.Eidam,B.K.Shoichet

Key ref:

R.S.Ferreira et al. (2010). Complementarity between a docking and a high-throughput screen in discovering new cruzain inhibitors. J Med Chem, 53, 4891-4905. PubMed id: 20540517

Date:

06-Nov-09 Release date: 07-Jul-10

Protein chain

P25779  (CYSP_TRYCR) -  Cruzipain from Trypanosoma cruzi

Seq: 467 a.a.

Struc: 215 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.22.51 - cruzipain.

J Med Chem 53:4891-4905 (2010)

PubMed id: 20540517

Complementarity between a docking and a high-throughput screen in discovering new cruzain inhibitors.

R.S.Ferreira, A.Simeonov, A.Jadhav, O.Eidam, B.T.Mott, M.J.Keiser, J.H.McKerrow, D.J.Maloney, J.J.Irwin, B.K.Shoichet.

ABSTRACT

Virtual and high-throughput screens (HTS) should have complementary strengths and weaknesses, but studies that prospectively and comprehensively compare them are rare. We undertook a parallel docking and HTS screen of 197861 compounds against cruzain, a thiol protease target for Chagas disease, looking for reversible, competitive inhibitors. On workup, 99% of the hits were eliminated as false positives, yielding 146 well-behaved, competitive ligands. These fell into five chemotypes: two were prioritized by scoring among the top 0.1% of the docking-ranked library, two were prioritized by behavior in the HTS and by clustering, and one chemotype was prioritized by both approaches. Determination of an inhibitor/cruzain crystal structure and comparison of the high-scoring docking hits to experiment illuminated the origins of docking false-negatives and false-positives. Prioritizing molecules that are both predicted by docking and are HTS-active yields well-behaved molecules, relatively unobscured by the false-positives to which both techniques are individually prone.