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 3 :: CDPK1 Virtual Screening
Develop a virtual screening model for a parasitology drug target, the calcium-dependent protein kinase 1 (CDPK1) of Eimeria tenella, based on known SAR and/or liganded structures of this target in different species (Toxoplasma gondii, Cryptosporidium parvum) and use the model to select the next set of compounds for screening in order to identify high quality chemical starting points for optimization in E.tenella CDPK1.
Workflow components:
Held-out test set: IC50 data on 22 compounds for C. parvum, T. gondii and E. tenella CDPK1.The experimental IC50 values for the 22 compounds of the held-out test set can be downloaded here (Excel spreadsheet; 2 tabs).
NOTE: Please use the following reference for the provided experimental IC50 values:
Portions of the data are “in press" in the journal PARASITOLOGY while the other parts are "in preparation for publication”. Authors are Katelyn R. Keyloun, Molly C. Reid, Ryan Choi, Yifan Song, Anna M.W. Fox, Heidi K. Hillesland , Zhongsheng Zhang, RamaSubbaRao Vidadala, Ethan A. Merritt, Audrey O.T. Lau, Dustin J. Maly, Erkang Fan, Lynn K. Barrett, Wesley C. Van Voorhis, and Kayode K. Ojo.
Discovery opportunity: Commitment from our partners at University of Washington to screen at least 100 compounds in the E. tenella CDPK1 biochemical assay for an overall winner.
Background
This project will help researchers develop inhibitors for CDPK1 of E. tenella, a major pathogen of chickens and other birds. This is a target of interest to TDT because of the “One Health” concept which is a worldwide strategy for expanding interdisciplinary collaborations and communications in all aspects of health care for humans, animals and the environment. CDPK1 has already been validated as a drug target in T. gondii and C. parvum, where it has been shown to be essential for entry of these obligate intracellular protozoan parasites into host cells, so that they cannot undergo replication. A series of inhibitors with high potency have been developed for T. gondii and C. parvum CDPK1 based on their small gatekeeper (Gly) in the ATP binding region of the active site, relying on a hydrophobic pocket that uniquely becomes available. However E. tenella CDPK1 has a larger gatekeeper (Thr) and aspects of the active site that make compounds designed for T. gondii and C. parvum less active.
Computational challenge and discovery opportunity
The challenge to the computational chemistry community is to develop a workflow based on available data that allows for the selection of a new set of compounds to screen that are predicted to be potent inhibitors of E. tenella CDPK1. Validation of computational methodology will come from comparing predictions of rank-order with a held-out test set for a set of ligands measured in the same CDPK1 target for T. gondii, C. Parvum and E. tenella. 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 in E. tenella CDPK1.
Input data-package
Crystal structures of CDPK1 from multiple species and published SAR
Files in data-package:
TDT2-challenge3-CDPK1_externalTestSet.txt: 22 compounds in held-out, external test set for validating the predictive model
Other data available from public sources and websites:
Crystal structures for CDPK1 from multiple species available from www.rcsb.org
SAR data for CDPK1 from multiple species available in publications; also some on https://www.ebi.ac.uk/chembl/
Relevant literature
Ojo KK, Larson ET, Keyloun KR, Castaneda LJ, Derocher AE, Inampudi KK, Kim JE, Arakaki TL, Murphy RC, Zhang L, Napuli AJ, Maly DJ, Verlinde CL, Buckner FS, Parsons M, Hol WG, Merritt EA, Van Voorhis WC. (2010) Toxoplasma gondii calcium-dependent protein kinase 1 is a target for selective kinase inhibitors. Nat Struct Mol Biol. 17:602-7. PMID: 20436472 PMCID: PMC2896873
Murphy RC, Ojo KK, Larson ET, Castellanos-Gonzalez A, Perera BG, Keyloun KR, Kim JE, Bhandari JG, Muller NR, Verlinde CL, White AC, Merritt EA, Van Voorhis WC, Maly DJ. (2010) Discovery of Potent and Selective Inhibitors of Calcium-Dependent Protein Kinase 1 (CDPK1) from C. parvum and T. gondii. (2010) ACS Med Chem Lett. 1(7):331-335. PMID: 21116453 PMCID: PMC2992447
Johnson SM, Murphy RC, Geiger JA, Derocher A, Zhang Z, Ojo K, Larson E, Perera BG, Dale E, He P, Fox A, Mueller N, Merritt EA, Fan E, Reid M, Parsons M, Van Voorhis WC, Maly DJ. (2012) Development of Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitors with Potent Anti-Toxoplasma Activity. J Med Chem. 55(5):2416-26. PMID: 22320388 PMCID: PMC3306180
Larson ET, Ojo KK, Murphy RC, Johnson SM, Zhang Z, Kim JE, Leibly DJ, Fox AM, Reid MC, Dale EJ, Perera BG, Kim J, Hewitt SN, Hol WG, Verlinde CL, Fan E, Van Voorhis WC, Maly DJ, Merritt EA. (2012) Multiple Determinants for Selective Inhibition of Apicomplexan Calcium-Dependent Protein Kinase CDPK1. J Med Chem. 55(6):2803-10. PMID: 22369268 PMCID: PMC3336864
Ojo KK, Pfander C, Mueller NR, Burstroem C, Larson ET, Bryan CM, Fox AMW, Reid MC, Johnson SM, Murphy RC, Kennedy M, Henning Mann H, Leibly DJ, Hewitt SN, Verlinde CLMJ. Kappe S, Merritt EA, Maly DJ, Billker O, Van Voorhis WC. (2012) Transmission of malaria to mosquitoes blocked by bumped kinase inhibitors. J. Clin. Invest. 122(6):2301–2305. doi: 10.1172/JCI61822 PMID:22565309 PMCID: PMC3366411
Zhang Z, Ojo KK, Johnson SM, Larson ET, He P, Geiger JA, Castellanos-Gonzalez A, White AC Jr, Parsons M, Merritt EA, Maly DJ, Verlinde CL, Van Voorhis WC, Fan E. (2012) Benzoylbenzimidazole-based selective inhibitors targeting Cryptosporidium parvum and Toxoplasma gondii calcium-dependent protein kinase-1. Bioorg Med Chem Lett. 22:5264-7. PMID: 22795629 PMCID: PMC3420979
Castellanos-Gonzalez A, A. White AC Jr, Ojo KK, Vidadala R, Zhang Z, Reid MC, Fox AMW, Keyloun KR, Rivas K, Irani A, Dann SM, Fan E, Maly DJ, Wesley C Van Voorhis. (2013). A novel Calcium Dependent Protein Kinase Inhibitor as a lead compound for treating Cryptosporidiosis. J Infect. Dis. PMID: 23878324 2013 Jul 21. [Epub ahead of print]
Ojo KK, Eastman RT, Vidadala R, Zhang Z, Rivas KL, Choi R, Lutz JD, Reid MC, Fox AMW, Hulverson MA, Kennedy M, Isoherranen N, Kim LM, Comess KM, Kempf DJ, Verlinde CLMJ, Su X-Z, Kappe S, Maly DJ, Fan E, & Van Voorhis WC. (2013) Specific inhibitor of PfCDPK4 blocks malaria transmission: Chemical-genetic validation. J Infect Dis. 2013 Oct 10. [Epub ahead of print] PMID: 24123773
Tasks to be covered in tutorial
1. Preparation of virtual screening models for CDPK1 in T. gondii, C. Parvum and E. tenella, including activity prediction (rank-order) for held-out external test set
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 E. tenella CDPK1. NOTE: At least 100 compounds from the winning submission will be acquired and tested in the E. tenella CDPK1 assay (partnership KK Ojo and WC van Voorhis, University of Washington); 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. Predictions for held-out, external test set against CDPK1 in T. gondii, C. parvum and E. tenella (identifier, smiles, and measure of predicted activity to allow rank-order)
2. Rank-ordered list of top-1000 commercial compounds predicted to be active against E. tenella CDPK1(identifier, smiles)
The Judging Criteria can be found here.
Challenge 3 :: CDPK1 Virtual Screening
Develop a virtual screening model for a parasitology drug target, the calcium-dependent protein kinase 1 (CDPK1) of Eimeria tenella, based on known SAR and/or liganded structures of this target in different species (Toxoplasma gondii, Cryptosporidium parvum) and use the model to select the next set of compounds for screening in order to identify high quality chemical starting points for optimization in E.tenella CDPK1.
Workflow components:
- Validation of the use of CDPK1 SAR and/or crystal structures from C. parvum [PDB ID: 3NCG] and T. gondii [PDB ID: 3I79] in virtual screening, including activity prediction of held-out test set
- Creation of a virtual screening model for E. tenella CDPK1 [NCBI Accession number CAA96439 (GI: 1279425)], including activity prediction of held-out test set
- Follow-up hit-finding: applying model to rank-order commercially available compounds for Eimeria tenella CDPK1
Held-out test set: IC50 data on 22 compounds for C. parvum, T. gondii and E. tenella CDPK1.The experimental IC50 values for the 22 compounds of the held-out test set can be downloaded here (Excel spreadsheet; 2 tabs).
NOTE: Please use the following reference for the provided experimental IC50 values:
Portions of the data are “in press" in the journal PARASITOLOGY while the other parts are "in preparation for publication”. Authors are Katelyn R. Keyloun, Molly C. Reid, Ryan Choi, Yifan Song, Anna M.W. Fox, Heidi K. Hillesland , Zhongsheng Zhang, RamaSubbaRao Vidadala, Ethan A. Merritt, Audrey O.T. Lau, Dustin J. Maly, Erkang Fan, Lynn K. Barrett, Wesley C. Van Voorhis, and Kayode K. Ojo.
Discovery opportunity: Commitment from our partners at University of Washington to screen at least 100 compounds in the E. tenella CDPK1 biochemical assay for an overall winner.
Background
This project will help researchers develop inhibitors for CDPK1 of E. tenella, a major pathogen of chickens and other birds. This is a target of interest to TDT because of the “One Health” concept which is a worldwide strategy for expanding interdisciplinary collaborations and communications in all aspects of health care for humans, animals and the environment. CDPK1 has already been validated as a drug target in T. gondii and C. parvum, where it has been shown to be essential for entry of these obligate intracellular protozoan parasites into host cells, so that they cannot undergo replication. A series of inhibitors with high potency have been developed for T. gondii and C. parvum CDPK1 based on their small gatekeeper (Gly) in the ATP binding region of the active site, relying on a hydrophobic pocket that uniquely becomes available. However E. tenella CDPK1 has a larger gatekeeper (Thr) and aspects of the active site that make compounds designed for T. gondii and C. parvum less active.
Computational challenge and discovery opportunity
The challenge to the computational chemistry community is to develop a workflow based on available data that allows for the selection of a new set of compounds to screen that are predicted to be potent inhibitors of E. tenella CDPK1. Validation of computational methodology will come from comparing predictions of rank-order with a held-out test set for a set of ligands measured in the same CDPK1 target for T. gondii, C. Parvum and E. tenella. 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 in E. tenella CDPK1.
Input data-package
Crystal structures of CDPK1 from multiple species and published SAR
Files in data-package:
TDT2-challenge3-CDPK1_externalTestSet.txt: 22 compounds in held-out, external test set for validating the predictive model
Other data available from public sources and websites:
Crystal structures for CDPK1 from multiple species available from www.rcsb.org
SAR data for CDPK1 from multiple species available in publications; also some on https://www.ebi.ac.uk/chembl/
Relevant literature
Ojo KK, Larson ET, Keyloun KR, Castaneda LJ, Derocher AE, Inampudi KK, Kim JE, Arakaki TL, Murphy RC, Zhang L, Napuli AJ, Maly DJ, Verlinde CL, Buckner FS, Parsons M, Hol WG, Merritt EA, Van Voorhis WC. (2010) Toxoplasma gondii calcium-dependent protein kinase 1 is a target for selective kinase inhibitors. Nat Struct Mol Biol. 17:602-7. PMID: 20436472 PMCID: PMC2896873
Murphy RC, Ojo KK, Larson ET, Castellanos-Gonzalez A, Perera BG, Keyloun KR, Kim JE, Bhandari JG, Muller NR, Verlinde CL, White AC, Merritt EA, Van Voorhis WC, Maly DJ. (2010) Discovery of Potent and Selective Inhibitors of Calcium-Dependent Protein Kinase 1 (CDPK1) from C. parvum and T. gondii. (2010) ACS Med Chem Lett. 1(7):331-335. PMID: 21116453 PMCID: PMC2992447
Johnson SM, Murphy RC, Geiger JA, Derocher A, Zhang Z, Ojo K, Larson E, Perera BG, Dale E, He P, Fox A, Mueller N, Merritt EA, Fan E, Reid M, Parsons M, Van Voorhis WC, Maly DJ. (2012) Development of Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitors with Potent Anti-Toxoplasma Activity. J Med Chem. 55(5):2416-26. PMID: 22320388 PMCID: PMC3306180
Larson ET, Ojo KK, Murphy RC, Johnson SM, Zhang Z, Kim JE, Leibly DJ, Fox AM, Reid MC, Dale EJ, Perera BG, Kim J, Hewitt SN, Hol WG, Verlinde CL, Fan E, Van Voorhis WC, Maly DJ, Merritt EA. (2012) Multiple Determinants for Selective Inhibition of Apicomplexan Calcium-Dependent Protein Kinase CDPK1. J Med Chem. 55(6):2803-10. PMID: 22369268 PMCID: PMC3336864
Ojo KK, Pfander C, Mueller NR, Burstroem C, Larson ET, Bryan CM, Fox AMW, Reid MC, Johnson SM, Murphy RC, Kennedy M, Henning Mann H, Leibly DJ, Hewitt SN, Verlinde CLMJ. Kappe S, Merritt EA, Maly DJ, Billker O, Van Voorhis WC. (2012) Transmission of malaria to mosquitoes blocked by bumped kinase inhibitors. J. Clin. Invest. 122(6):2301–2305. doi: 10.1172/JCI61822 PMID:22565309 PMCID: PMC3366411
Zhang Z, Ojo KK, Johnson SM, Larson ET, He P, Geiger JA, Castellanos-Gonzalez A, White AC Jr, Parsons M, Merritt EA, Maly DJ, Verlinde CL, Van Voorhis WC, Fan E. (2012) Benzoylbenzimidazole-based selective inhibitors targeting Cryptosporidium parvum and Toxoplasma gondii calcium-dependent protein kinase-1. Bioorg Med Chem Lett. 22:5264-7. PMID: 22795629 PMCID: PMC3420979
Castellanos-Gonzalez A, A. White AC Jr, Ojo KK, Vidadala R, Zhang Z, Reid MC, Fox AMW, Keyloun KR, Rivas K, Irani A, Dann SM, Fan E, Maly DJ, Wesley C Van Voorhis. (2013). A novel Calcium Dependent Protein Kinase Inhibitor as a lead compound for treating Cryptosporidiosis. J Infect. Dis. PMID: 23878324 2013 Jul 21. [Epub ahead of print]
Ojo KK, Eastman RT, Vidadala R, Zhang Z, Rivas KL, Choi R, Lutz JD, Reid MC, Fox AMW, Hulverson MA, Kennedy M, Isoherranen N, Kim LM, Comess KM, Kempf DJ, Verlinde CLMJ, Su X-Z, Kappe S, Maly DJ, Fan E, & Van Voorhis WC. (2013) Specific inhibitor of PfCDPK4 blocks malaria transmission: Chemical-genetic validation. J Infect Dis. 2013 Oct 10. [Epub ahead of print] PMID: 24123773
Tasks to be covered in tutorial
1. Preparation of virtual screening models for CDPK1 in T. gondii, C. Parvum and E. tenella, including activity prediction (rank-order) for held-out external test set
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 E. tenella CDPK1. NOTE: At least 100 compounds from the winning submission will be acquired and tested in the E. tenella CDPK1 assay (partnership KK Ojo and WC van Voorhis, University of Washington); 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. Predictions for held-out, external test set against CDPK1 in T. gondii, C. parvum and E. tenella (identifier, smiles, and measure of predicted activity to allow rank-order)
2. Rank-ordered list of top-1000 commercial compounds predicted to be active against E. tenella CDPK1(identifier, smiles)
The Judging Criteria can be found here.