How Frequently Are Pan-Assay Interference Compounds Active? Large-Scale Analysis of Screening Data Reveals Diverse Activity Profiles, Low Global Hit Frequency, and Many Consistently Inactive Compounds

Journal of Medicinal Chemistry

Volumn 60, Issue 9, 2017, Pages 3879-3886

  Jasial, Swarit ^a   Hu, Ye ^a   Bajorath, Jürgen ^a  

^a UNIVERSITY OF BONN   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

BEHAVIOR; SCREENING TEST; BIOASSAY; DRUG DEVELOPMENT; HIGH THROUGHPUT SCREENING; MEDICINAL CHEMISTRY;

BIOLOGICAL ASSAY; CHEMISTRY, PHARMACEUTICAL; DRUG DISCOVERY; HIGH-THROUGHPUT SCREENING ASSAYS;

EID: 85019243380     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.7b00154     Document Type: Article

References (22)

1. Baell, J. B.; Holloway, G. A. New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays J. Med. Chem. 2010, 53, 2719-2740 10.1021/jm901137j
2. Baell, J. B.; Ferrins, L.; Falk, H.; Nikolakopoulos, G. PAINS: Relevance to Tool Compound Discovery and Fragment-Based Screening Aust. J. Chem. 2013, 66, 1483-1494 10.1071/CH13551
3. Baell, J.; Walters, M. A. Chemistry: Chemical Con Artists Foil Drug Discovery Nature 2014, 513, 481-483 10.1038/513481a
4. Nelson, K. M.; Dahlin, J. L.; Bisson, J.; Graham, J.; Pauli, G. F.; Walters, M. A. The Essential Medicinal Chemistry of Curcumin J. Med. Chem. 2017, 60, 1620-1637 10.1021/acs.jmedchem.6b00975
5. Gilberg, E.; Jasial, S.; Stumpfe, D.; Dimova, D.; Bajorath, J. Highly Promiscuous Small Molecules from Biological Screening Assays Include Many Pan-Assay Interference Compounds but Also Candidates for Polypharmacology J. Med. Chem. 2016, 59, 10285-10290 10.1021/acs.jmedchem.6b01314
6. Baell, J. B. Feeling Nature’s PAINS: Natural Products, Natural Product Drugs, and Pan Assay Interference Compounds (PAINS) J. Nat. Prod. 2016, 79, 616-628 10.1021/acs.jnatprod.5b00947
7. Bisson, J.; McAlpine, J. B.; Friesen, J. B.; Chen, S. N.; Graham, J.; Pauli, G. F. Can Invalid Bioactives Undermine Natural Product-Based Drug Discovery? J. Med. Chem. 2016, 59, 1671-1690 10.1021/acs.jmedchem.5b01009
8. Dahlin, J. L.; Nissink, J. W.; Strasser, J. M.; Francis, S.; Higgins, L.; Zhou, H.; Zhang, Z.; Walters, M. A. PAINS in the Assay: Chemical Mechanisms of Assay Interference and Promiscuous Enzymatic Inhibition Observed during a Sulfhydryl-Scavenging HTS J. Med. Chem. 2015, 58, 2091-2113 10.1021/jm5019093
9. Dahlin, J. L.; Nissink, J. W.; Francis, S.; Strasser, J. M.; John, K.; Zhang, Z.; Walters, M. A. Post-HTS Case Report and Structural Alert: Promiscuous 4-Aroyl-1,5-Disubstituted-3-Hydroxy-2H-Pyrrol-2-One Actives Verified by ALARM NMR Bioorg. Med. Chem. Lett. 2015, 25, 4740-4752 10.1016/j.bmcl.2015.08.020
10. Kilchmann, F.; Marcaida, M. J.; Kotak, S.; Schick, T.; Boss, S. D.; Awale, M.; Gönczy, P.; Reymond, J. L. Discovery of a Selective Aurora A Kinase Inhibitor by Virtual Screening J. Med. Chem. 2016, 59, 7188-7211 10.1021/acs.jmedchem.6b00709
11. Aldrich, C.; Bertozzi, C.; Georg, G. I.; Kiessling, L.; Lindsley, C.; Liotta, D.; Merz, K. M., Jr.; Schepartz, A.; Wang, S. The Ecstasy and Agony of Assay Interference Compounds ACS Cent. Sci. 2017, 3, 143-147 10.1021/acscentsci.7b00069
12. Jadhav, A.; Ferreira, R. S.; Klumpp, C.; Mott, B. T.; Austin, C. P.; Inglese, J.; Thomas, C. J.; Maloney, D. J.; Shoichet, B. K.; Simeonov, A. Quantitative Analyses of Aggregation, Autofluorescence, and Reactivity Artifacts in a Screen for Inhibitors of a Thiol Protease J. Med. Chem. 2010, 53, 37-51 10.1021/jm901070c
13. Feng, B. Y.; Simeonov, A.; Jadhav, A.; Babaoglu, K.; Inglese, J.; Shoichet, B. K.; Austin, C. P. A High-Throughput Screen for Aggregation-Based Inhibition in a Large Compound Library J. Med. Chem. 2007, 50, 2385-2390 10.1021/jm061317y
14. Babaoglu, K.; Simeonov, A.; Irwin, J. J.; Nelson, M. E.; Feng, B.; Thomas, C. J.; Cancian, L.; Costi, M. P.; Maltby, D. A.; Jadhav, A.; Inglese, J.; Austin, C. P.; Shoichet, B. K. Comprehensive Mechanistic Analysis of Hits from High-Throughput and Docking Screens Against Beta-Lactamase J. Med. Chem. 2008, 51, 2502-2511 10.1021/jm701500e
15. Ferreira, R. S.; Simeonov, A.; Jadhav, A.; Eidam, O.; Mott, B. T.; Keiser, M. J.; McKerrow, J. H.; Maloney, D. J.; Irwin, J. J.; Shoichet, B. K. Complementarity Between a Docking and a High-Throughput Screen in Discovering New Cruzain Inhibitors J. Med. Chem. 2010, 53, 4891-4905 10.1021/jm100488w
16. Capuzzi, S. J.; Muratov, E. N.; Tropsha, A. Phantom PAINS: Problems with the Utility of Alerts for Pan-Assay INterference CompoundS J. Chem. Inf. Model. 2017, 57, 417-427 10.1021/acs.jcim.6b00465
17. Wang, Y.; Xiao, J.; Suzek, T. O.; Zhang, J.; Wang, J.; Zhou, Z.; Han, L.; Karapetyan, K.; Dracheva, S.; Shoemaker, B. A.; Bolton, E.; Gindulyte, A.; Bryant, S. H. PubChem’s BioAssay Database Nucleic Acids Res. 2012, 40, D400-D412 10.1093/nar/gkr1132
18. RDKit: Cheminformatics and Machine Learning Software (2013). http://www.rdkit.org.
19. Sterling, T.; Irwin, J. J. ZINC 15--Ligand Discovery for Everyone J. Chem. Inf. Model. 2015, 55, 2324-2337 10.1021/acs.jcim.5b00559
20. Gaulton, A.; Bellis, L. J.; Bento, A. P.; Chambers, J.; Davies, M.; Hersey, A.; Light, Y.; McGlinchey, S.; Michalovich, D.; Al-Lazikani, B.; Overington, J. P. ChEMBL: A Large-Scale Bioactivity Database for Drug Discovery Nucleic Acids Res. 2012, 40, D1100-D1107 10.1093/nar/gkr777
21. Saubern, S.; Guha, R.; Baell, J. B. KNIME Workflow to Asses PAINS Filters in SMARTS Format. Comparison of RDKit and Indigo Chemoinformatics Libraries Mol. Inf. 2011, 30, 847-850 10.1002/minf.201100076
22. http://www.zenodo.org.