Teach – Discover – Treat: A COMP initiative to provide high quality computational chemistry tutorials that impact education and drug discovery for neglected diseases http://www.TDTproject.org
Challenge 2 :: Discover new anti-Malaria compounds
Use the apo structure of a validated Malaria target, Lysyl tRNA synthetase, to select the next set of compounds for screening in order to identify high quality chemical starting points for optimization.
Workflow components:
Held-out test set: Screening data and selected IC50s for compounds in TCAMS (Tres Cantos Anti Malarial Set).
Discovery opportunity: Commitment from our partners at the Structural Genomics Consortium (Toronto) to screen at least 100 compounds in the Lysyl tRNA synthetase biochemical assay for an overall winner.
Background
Pf Krs1 - (Lysyl tRNA synthetase, PF3D7_1350100) is a well validated target for malaria whose apo-structure was published in 2013 and for which cladosporin is the only known selective hit, which 'chemically validates' the target. Cladosporin is potently active on both blood and liver stages of P falciparum infection. The co-crystal structure of Cladosporin with Pf Krs1 has not yet been solved. New drug-like chemical leads for this target would be very attractive as potential leads for anti-malaria drug-discovery. The TDT partners at SGC Toronto are setting up a biochemical assay for Pf Krs1 and will screen the TCAMS (Tres Cantos Anti Malarial Set; this is a collection of hits from Pf whole cell screening).
Computational challenge and discovery opportunity
The challenge to the computational chemistry community is to develop a workflow based on the available data that allows for the selection of a new set of compounds to screen for Pf Krs1. Comparing the hits from the Pf Krs1 biochemical screen with computationally predicted hits will be a useful validation of computational methodology. Successful approaches can be used to screen larger, more diverse commercially available sets and if an overall winner is identified, their selected compounds will be screened against Pf Krs1. Computationally-derived binding poses for cladosporin could be compared with a co-crystal structure if that becomes available in the right time frame.
Input data:
Crystal structure of Plasmodium Falciparum Lysyl tRNA synthetase and structure of published inhibitor, Cladosporin
Input data-package
The information on this webpage with all other data available from public websites
1. Crystal structure for apo enzyme with PDB ID: 4h02 from www.pdb.org
2. Held-out test set is the GSK TCAMS, available from either https://www.ebi.ac.uk/chemblntd or https://www.collaborativedrug.com/
Relevant literature
Target validation, including Cladosporin chemical structure:
Cell Host Microbe. 2012 Jun 14;11(6):654-63. http://doi.org/10.1016/j.chom.2012.04.015
Crystal structure of apo enzyme:
Acta Crystallogr D Biol Crystallogr. 2013 May;69(Pt 5):785-95. http://doi.org/10.1107/S0907444913001923
Tasks to be covered in tutorial
1. Preparation of crystal structure for virtual screening, including
a) Generation of binding pose for Cladosporin (inhibitor published in target validation paper above)
b) Activity prediction for held-out external test set: download TCAMS from sources mentioned above. Experimental data will be available for this set and will be used to judge the quality of this submission.
2. Follow-up hit finding
a) Download most recent file of commercially available compounds from eMolecules, http://downloads.emolecules.com/ordersc/ and select most recent directory. We recommend you download this in January 2014 for good availability; use the “parent” file (without salts and solvates)
b) Rank-order commercial compounds based on predicted activity against Pf Krs1 NOTE: At least 100 compounds from the winning submission will be acquired and tested in the Lysyl tRNA synthetase assay (partnership Chris Walpole, SGC Toronto); we ask that you submit a rank-ordered list of 1000 compounds from the eMolecules file.
Submission package
Submit your tutorial and data here: http://file.teach-discover-treat.org/submit/index.php
Specific files to include for this challenge
1. PDB file with the Pf Krs1 protein and predicted binding mode for cladosporin
2. Predictions for held-out, external test set in Pf Krs1 (identifier, smiles, measure of predicted activity)
3. Rank-ordered list of top-1000 commercial compounds predicted to be active (identifier, smiles)
The Judging Criteria can be found here.
Challenge 2 :: Discover new anti-Malaria compounds
Use the apo structure of a validated Malaria target, Lysyl tRNA synthetase, to select the next set of compounds for screening in order to identify high quality chemical starting points for optimization.
Workflow components:
- Preparation of crystal structure for virtual screening, including generation of binding pose for Cladosporin (published inhibitor) and activity prediction for held-out test set
- Follow-up hit-finding: applying model to rank-order commercially available compounds
Held-out test set: Screening data and selected IC50s for compounds in TCAMS (Tres Cantos Anti Malarial Set).
Discovery opportunity: Commitment from our partners at the Structural Genomics Consortium (Toronto) to screen at least 100 compounds in the Lysyl tRNA synthetase biochemical assay for an overall winner.
Background
Pf Krs1 - (Lysyl tRNA synthetase, PF3D7_1350100) is a well validated target for malaria whose apo-structure was published in 2013 and for which cladosporin is the only known selective hit, which 'chemically validates' the target. Cladosporin is potently active on both blood and liver stages of P falciparum infection. The co-crystal structure of Cladosporin with Pf Krs1 has not yet been solved. New drug-like chemical leads for this target would be very attractive as potential leads for anti-malaria drug-discovery. The TDT partners at SGC Toronto are setting up a biochemical assay for Pf Krs1 and will screen the TCAMS (Tres Cantos Anti Malarial Set; this is a collection of hits from Pf whole cell screening).
Computational challenge and discovery opportunity
The challenge to the computational chemistry community is to develop a workflow based on the available data that allows for the selection of a new set of compounds to screen for Pf Krs1. Comparing the hits from the Pf Krs1 biochemical screen with computationally predicted hits will be a useful validation of computational methodology. Successful approaches can be used to screen larger, more diverse commercially available sets and if an overall winner is identified, their selected compounds will be screened against Pf Krs1. Computationally-derived binding poses for cladosporin could be compared with a co-crystal structure if that becomes available in the right time frame.
Input data:
Crystal structure of Plasmodium Falciparum Lysyl tRNA synthetase and structure of published inhibitor, Cladosporin
Input data-package
The information on this webpage with all other data available from public websites
1. Crystal structure for apo enzyme with PDB ID: 4h02 from www.pdb.org
2. Held-out test set is the GSK TCAMS, available from either https://www.ebi.ac.uk/chemblntd or https://www.collaborativedrug.com/
Relevant literature
Target validation, including Cladosporin chemical structure:
Cell Host Microbe. 2012 Jun 14;11(6):654-63. http://doi.org/10.1016/j.chom.2012.04.015
Crystal structure of apo enzyme:
Acta Crystallogr D Biol Crystallogr. 2013 May;69(Pt 5):785-95. http://doi.org/10.1107/S0907444913001923
Tasks to be covered in tutorial
1. Preparation of crystal structure for virtual screening, including
a) Generation of binding pose for Cladosporin (inhibitor published in target validation paper above)
b) Activity prediction for held-out external test set: download TCAMS from sources mentioned above. Experimental data will be available for this set and will be used to judge the quality of this submission.
2. Follow-up hit finding
a) Download most recent file of commercially available compounds from eMolecules, http://downloads.emolecules.com/ordersc/ and select most recent directory. We recommend you download this in January 2014 for good availability; use the “parent” file (without salts and solvates)
b) Rank-order commercial compounds based on predicted activity against Pf Krs1 NOTE: At least 100 compounds from the winning submission will be acquired and tested in the Lysyl tRNA synthetase assay (partnership Chris Walpole, SGC Toronto); we ask that you submit a rank-ordered list of 1000 compounds from the eMolecules file.
Submission package
Submit your tutorial and data here: http://file.teach-discover-treat.org/submit/index.php
Specific files to include for this challenge
1. PDB file with the Pf Krs1 protein and predicted binding mode for cladosporin
2. Predictions for held-out, external test set in Pf Krs1 (identifier, smiles, measure of predicted activity)
3. Rank-ordered list of top-1000 commercial compounds predicted to be active (identifier, smiles)
The Judging Criteria can be found here.