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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 histocompatiability 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 presentation. [1-3].
2018-01-16 | Cathepsin S Stage 2 answers updated for siginificant digits |
2017-11-19 | Cathepsin S Deadline - Dec 15, 2017 23:59PST |
2017-11-13 | A sharp-eyed participant has correctly pointed out that compound CatS_23 is identical to CatS_102. Janssen lists these as having the same IC50, as anticipated. To avoid bookkeeping complexities, we will ask that you include both compounds in the submission files. |
2017-10-16 | Submissions are now being accepted for Stage 1B with a closing date/time of 2017-10-23 23:59PST. |
2017-10-12 | Submission instructions, which includes template and example files are online now. |
2017-10-10 | A correction was made to the Stage 1B data download. The new docking_structures_stage1B_REVISED_20171010.tgz file fixed the PDBID of CatS_10, which should be "WCGQ" |
2017-10-09 | A new Stage 1b docking component, closing October 23, has been added. Go here for details. |
2017-09-28 | If you use the crystal structures provided in the GC3 data package for docking, please construct your Pose filenames with the following temporary PDB IDS: CAT1 for the SO4 structure and CAT2 for the DMSO structure. |
2017-09-26 | A minor change to the "CatS_initial_packet_to_participants_REVISED_20170921.zip" has been made. The line breaks of the "CatS_pose_compounds_D3R_GC3.csv" file were updated and saved to a new "CatS_initial_packet_to_participants_REVISED_20170926.zip". |
2017-09-21 | Our rerefinement of the Cathepsin S crystal structures revealed that three ligands for which the SMILES strings we were given listed a trimethyl group actually have a trifluoro group. We confirmed this correction with Janssen. The compounds are CatS_7, Cat_9, and CatS_14. |
2017-09-21 | Submission instructions, which includes template and example files are online now. |
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.
This folder contains 24 CatS crystallographic structures for docking, in addition to a CSV file containing mappings between ligand IDs and structure IDs:
File CatS_ligandID_structureID.csv displays which ligand was crystallized with each structure ID.
Files in structure ID files are labeled by the following syntax: pdbid-CatS_chain#.pdb
All structure ID files were aligned to chain A of the gabj structure.
This folder contains 24 refined CatS crystallographic structures provided to D3R from Janssen and re-refined by D3R crystallographers, in addition to a CSV file containing mappings between ligand IDs and structure IDs: File CatS_ligandID_structureID.csv displays which ligand was crystallized with each srtucture ID. Structure files were aligned to the chain A of the gabj structure.
For each of the 24 CatS crystallographic structures,
CatS_crystal_structures/ contains all 24 re-refined CatS crystal structures
ChainA/ contains unique files for each A chain from the 24 re-refined CatS crystal structures
chainB/ contains unique files for each B chain from the 24 re-refined CatS crystal structures
chainC/ contains unique files for each C chain from the 24 re-refined CatS crystal structures
chainD/ contains unique files for each D chain from the 24 re-refined CatS crystal structures
Template and Example packet: CatS-stage2_Submission_examples_and_templates.zip
General instructions on what to include in each subchallenge component can be found at https://drugdesigndata.org/about/grand-challenge-3-submission-instructions.
This packet includes "templates" and "examples" folders.
The "template" folder includes files where values have been removed.
The "examples" folder includes complete submissions that passed validation:
- scorestructure.tgz
- scoreligand.tgz
- freeenergy.tgz
Note: the data in the example TGZ files are merely for demonstration purposes and hold no scientific value.
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 histocompatiability 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 presentation. [1-3].
This data set comprises non-peptidic, non-covalent, small molecule inhibitors across a three order of magnitude range (nM to μM) of IC50s for CatS. Specifically, we provide 136 CatS inhibitors for affinity prediction, 24 for pose prediction, and 33 for free energy prediction.
The conformation of the CatS binding pocket can change, depending on the nature of the bound ligand. In particular, Phe211 in the S2 pocket adopts a different conformation, depending on the size of the P2 moiety of the ligand [4]. If the P2 moiety is small, Phe211 swings into a conformation that closes the entrance to the deeper part of the S2 pocket. However, a larger P2 moiety can induce Phe211 to swing open, allowing for ligand binding to the deeper portion of the S2 pocket [5].
For details of the binding assays, we were referred to publications from the Janssen group, which describe the following binding assays conditions [6]:
"In general, the assays were run using fluorescence resonance energy transfer-based substrates. For example, the cathepsin S, L, and L2 assays used the substrate (Aedens)EK ARVLAEAA(Dabcyl)K-amide and cathepsin S cleaves between amino acids Leu-6 and Ala-7. The fluorescence of the aedens group is quenched by the dabcyl moiety in the intact peptide. Upon cleavage by cathepsin S, the quenching is released and the fluorescence of the aedens group can be measured.
The cysteine CatS assays were run in 100-μl volume with a buffer consisting of 100 mM sodium acetate, pH 5.0, containing 100 mM NaCl and 1 mM dithiothreitol, except for cathepsin Z, which used 10 mM dithiothreitol and cathepsins E, D, and napsin where no dithiothreitol was present. The enzymes were mixed with 7.5 ml of buffer and then 75 μl was added to a Dynax black Mi- crofluor 2 plate. To this, 5 μl of a 20 μl solution of compound in 30% DMSO was added. This was followed by the addition of 20 μl of 5X substrate to initiate the reaction. In all cases, an 11 point 1:2 dilution of the compound was used at seven substrate concentrations (also 1:2). The increase in fluorescence was measured on a Cytofluor II (Applied Biosystems, Foster City, CA) with an excitation filter of 360/40 nm and an emission filter of 460/40 nm. A reading was made every minute for 20 to 60 min, depending on the assay, and the slope obtained from a linear regression of this time course was used as the reaction rate."
The structure files provided by Janssen, did not specify crystallization conditions. However, manuscripts provided to us that discuss PDB IDs 3iej, 3mpe, and 3kwn, list the following [1-3]:
"Crystallization conditions: 100MM sodium acetate, pH 4.5, 200mm ammonium acetate, 25% PEG 8000. Protein concentration 7 mg/ml, vapor diffusion, sitting drop, temperature 293 K."
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. Pauly TA, Sulea T, Ammirati M, et al (2003) Specificity Determinants of Human Cathepsin S Revealed by Crystal Structures of Complexes,. Biochemistry (Mosc) 42:3203-3213. doi: 10.1021/bi027308i
5. Markt P, McGoohan C, Walker B, et al (2008) Discovery of Novel Cathepsin S Inhibitors by Pharmacophore-Based Virtual High-Throughput Screening. J Chem Inf Model 48:1693-1705. doi: 10.1021/ci800101j
6. 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
This section presents metrics of the ability of the predictions to correctly rank ligands by affinity. The rankings were evaluated in terms of the Kendall's τ, Spearman's ρ, and estimated binding energies for the free energy sets were additionally evaluated in terms of centered root-mean-square error (RMSEc, kcal/mol) and Pearson's r. Uncertainties in these statistics (e.g., Kendall's τ Errors in the table) were obtained by recomputing them in 10,000 rounds of resampling with replacement, where, in each sample, the experimental IC50 or Kd data were randomly modified based on the experimental uncertainties. Experimental uncertainties are added to the free energy, ΔG, as a random offset δG drawn from a Gaussian distribution of mean zero and standard deviation RTln(Ierr). In this evaluation, the value of Ierr was set to 2.5.
For the kinases, a number of experimental Kd values were reported as ≥10 µM, making them difficult to include in standard metrics of ranking accuracy, so these cases were excluded from these affinity ranking assessments. However, they are included in the Active/Inactive Classification assessments, below.
GC3_CatS1A.tgz (508M)
GC3_CatS1B.tgz (184M)
GC3_CatS2.tgz (554M)
GC3_vegfr2_submissions.tgz (179M)
GC3_tie2_submissions.tgz (7.7M)
GC3_p38a_submissions.tgz (141M)
GC3_jak2sc2_submissions.tgz (210M)
GC3_jak2sc3_submissions.tgz (63M)
GC3_abl1_submissions.tgz (108M)