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BioAssay: AID 2413

Probe Summary: Docking False Negative Inhibitors of Cruzain

Chagas Disease is a neglected tropical disease that affects over 16 million people in Latin America. The cysteine protease cruzain is essential for the survival Trypanosoma cruzi, the parasitic agent responsible for Chagas disease. Potential intervention for T. cruzi includes the inhibition of cruzain. This bioassay will summarize the ongoing development of small molecule cruzain inhbitiors. Currently, a screen of ~200k compounds were screened in a concentration-dependent manner and several inhibitors have been identified with the potential for lead development. ..more
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AID: 2413
Data Source: NCGC (CRUZ102)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Screening Center Network
Deposit Date: 2010-02-24
Target
Related Experiments
AIDNameTypeComment
1476qHTS Assay for Promiscuous and Specific Inhibitors of Cruzain (without detergent)Confirmatorydepositor-specified cross reference: qHTS Assay for Promiscuous and Specific Inhibitors of Cruzain (without detergent)
1478qHTS Assay for Promiscuous and Specific Inhibitors of Cruzain (with detergent)Confirmatorydepositor-specified cross reference: qHTS Assay for Promiscuous and Specific Inhibitors of Cruzain (with detergent)
2158Confirmation qHTS Assay for Inhibitors of CruzainConfirmatorydepositor-specified cross reference: Confirmation qHTS Assay for Inhibitors of Cruzain
2161qHTS Assay for Inhibitors of Papain: Counterscreen for Cruzain AssayConfirmatorydepositor-specified cross reference: qHTS Assay for Inhibitors of Papain: Counterscreen for Cruzain Assay
2249Probe Development Summary of Promiscuous Inhibitors (Artifacts) of CruzainSummarydepositor-specified cross reference: Probe Development Summary of Promiscuous Inhibitors (Artifacts) of Cruzain
2737Confirmation Competitive Binding Assay for Inhibitors of CruzainConfirmatorysame project related to Summary assay
493215Inhibitors of Cruzain: Benzimidazole Series - Round 1Confirmatorysame project related to Summary assay
504656Inhibitors of Cruzain: Trypanosoma Cruzi Growth Inhibition AssayConfirmatorysame project related to Summary assay
Description:
Chagas Disease is a neglected tropical disease that affects over 16 million people in Latin America. The cysteine protease cruzain is essential for the survival Trypanosoma cruzi, the parasitic agent responsible for Chagas disease. Potential intervention for T. cruzi includes the inhibition of cruzain. This bioassay will summarize the ongoing development of small molecule cruzain inhbitiors. Currently, a screen of ~200k compounds were screened in a concentration-dependent manner and several inhibitors have been identified with the potential for lead development.

In addition to development of small molecule therapeutics for Chagas Disease, a major objective in this project was to compare a large scale qHTS with a prospective virtual screen. The screening collection was docked using the DOCK program from Professor Shoichet's Lab, and top virtual screening hits were compared with non-covalent reversible inhibitors resulting from the Cruzain qHTS.

Of particular interest was a drug-like series that gave a low docking score but was active in the primary qHTS. One member of this series was co-crystalized and shown to be a true reversible inhibitor of cruzain.

This assay will summarize the SAR around this docking "false negative" series. Future update will also include the deposition of the cruzain structure bound to a member of this series.

See following references for additional details:

Jadhav A, et al. J Med Chem. 2010 Jan 14;53(1):37-51.
Mott BT, et al. J Med Chem. 2010 Jan 14;53(1):52-60.

Assay Provider: Shoichet, Brian; University of California, San Francisco
Screening Center PI: Austin, C.P.
Screening Center: NIH Chemical Genomics Center [NCGC]
Protocol
Please see related AIDs for individual BioAssay additional details: 1476, 1478, 2158, 2161, 2249
Comment
Keywords: NIH Roadmap, MLSCN, MLI, MLSMR, qHTS, NCGC, Cruzain, Cruzipain, Aggregation, Chagas disease, Docking False Negative
Compound ranking comments will be provided here as small molecule probes are developed and are updated with results in PubChem.
Categorized Comment - additional comments and annotations
From MLP Probe Report:
Probe count: 1
MLP Probe ML# for probe 1: ML217
PubChem Substance ID (SID) for probe 1: 104219746
PubChem Compound ID (CID) for probe 1: 3159995
NCBI Book chapter link for probe 1: http://www.ncbi.nlm.nih.gov/books/NBK133417/ (ID: 3026100)
Grant number for probe 1: DA024891-01
NCBI Book chapter title for probe 1: Reversible and non-covalent benzimidazole-based in vivo lead for Chagas disease
Additional Information
Grant Number: DA024891-01

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