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Cathepsin_S - Overview

Challenge timeframe: Sep 04, 2018 to Dec 04, 2018


Updates

2018-12-07 - Answers to the challenges are now available: CatS_score_compounds_D3R_GC4_answers.csv and CatS_FEset_compounds_D3R_GC4_answers.csv

2018-11-27 - Submissions are now being accepted. Note: structure based scoring files that exceed 20M will likely not work for now. In the meantime, please upload your file to a public server like box.com, google drive and email us the download link. In it's place, please upload a smaller version to the D3R website that we can manually replace.

2018-11-26 - Template and example files are ready for download

2018-10-29 - Please note that the CatS ligands numbering in the free energy and scoring sets are offset by one.

A sharp-eyed participant noticed that the names of the ligands in the CatS free energy sets don't match those in the full scoring set. Please keep the naming as is; we will account for the discrepancy in the evaluation process.

Stage 1 - Dataset packet provided: CatS_initial_packet_to_participants.zip
  • CatS_target_D3R_GC4.fasta: Protein sequence file of the Cathepsin S construct used.
  • CatS_score_compounds_D3R_GC4.csv: CSV file of 459 compounds and their corresponding SMILES string.
  • CatS_FESet_compounds_D3R_GC4.csv: CSV file of 39 compounds selected from CatS_score_compounds_D3R_GC4.csv for explicit-solvent relative or absolute free energy calculations.

Note: No attempt was made to set appropriate starting conformations or optimal protonation or tautomer states for the ligands, or to generate alternative tautomer states. It is up to you to choose and set these states for your calculations.

Introduction to Cathepsin S

The cathepsins constitute an 11-member family of proteases involved in protein degradation. Cathepsin S is highly expressed in antigen-presenting cells, where it degrades major histocompatibility complex class II (MHC II)-associated invariant chain. CatS is a candidate target for regulating immune hyper-responsiveness, as the inhibition of CatS may limit antigen presentation1-3.

This data set comprises a follow-on challenge to GC3, consisting of non-peptidic, non-covalent, small molecule inhibitors across a three order of magnitude range (nM to μM) of IC50s for CatS. Specifically, we provide 459 CatS inhibitors for affinity prediction, and 39 molecules for free energy prediction. This dataset was kindly donated by Janssen. Please note the affinity values from this set were measured against a C25S CatS mutant.

CatS.png
Representative crystal structures of CatS (PDB 2HHN).

Cathepsin S Binding assay conditions

For details of the binding assays, we were referred to publications from the Janssen group, which describe the following binding assays conditions4

References

  1. Ameriks MK, Bembenek SD, Burdett MT, et al (2010) Diazinones as P2 replacements for pyrazole-based cathepsin S inhibitors. Bioorg Med Chem Lett 20:4060-4064. doi: 10.1016/j.bmcl.2010.05.086
  2. Wiener DK, Lee-Dutra A, Bembenek S, et al (2010) Thioether acetamides as P3 binding elements for tetrahydropyrido-pyrazole cathepsin S inhibitors. Bioorg Med Chem Lett 20:2379-2382. doi: 10.1016/j.bmcl.2010.01.103
  3. Ameriks MK, Axe FU, Bembenek SD, et al (2009) Pyrazole-based cathepsin S inhibitors with arylalkynes as P1 binding elements. Bioorg Med Chem Lett 19:6131-6134. doi: 10.1016/j.bmcl.2009.09.014
  4. Thurmond RL, Sun S, Sehon CA, et al (2004) Identification of a Potent and Selective Noncovalent Cathepsin S Inhibitor. J Pharmacol Exp Ther 308:268-276. doi: 10.1124/jpet.103.056879

Cathepsin_S - Data Download

Challenge timeframe: Sep 04, 2018 to Dec 04, 2018


Stage 1 (09/04/2018 to 12/04/2018)
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Cathepsin_S - Protocols

Challenge timeframe: Sep 04, 2018 to Dec 04, 2018


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Cathepsin_S - Submissions

Challenge timeframe: Sep 04, 2018 to Dec 04, 2018


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Cathepsin_S - Evaluation Results

Challenge timeframe: Sep 04, 2018 to Dec 04, 2018


Evaluation Results

Evaluation results are not available yet.
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