So you want to do a chemicalscreen?
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This document summarizes a workshop on screening models for the 13th Annual IZFS Meeting in Madison, Wisconsin on June 23rd, 2018. The workshop outline covers decisions and design in screening, execution and considerations, and next steps after screening. The document discusses different types of screening models including morphological, pathway, transgene assisted, therapeutic, and behavioral screens. It also covers common commercial screening libraries, planning a screen, desirable qualities in hits, prioritizing hits, target deconvolution approaches, and cheminformatics resources. The workshop included exercises for participants to plan a screen, cluster hit compounds, and identify potential vendors.
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So you want to do a chemicalscreen?
- 1. Chairs: Charles “Chuck” Williams & Charles “Chaz” Hong Workshop: 13th Annual IZFS Meeting Madison, Wisconsin June 23rd 2018
- 3. Outline • Upfront – Decisions and design • Nuts and Bolts – Execution and considerations • Screen done. What next? – Follow up and next steps • Questions/Panel(~30 minutes)
- 5. Why are we doing it? It sounded good in a grant Establish proof of concept to “sell” the screen itself (platform centric) Find and develop a molecule to use as a tool Find a scaffold to build on for a therapeutic to take to clinic Log(Difficulty)
- 6. Types of screens • Morphological • Pathway • Transgene Assisted • Therapeutic • Behavioral
- 7. Morphological Screen Williams et al 2015, Hong et al 2008
- 8. Pathway Screen Le et al 2013; Nishiya et al 2014
- 9. Transgene Assisted Screen Ni et al 2013; Molina et al 2007
- 10. Therapeutic Screen Liu et al 2014; Zhang et al 2014
- 11. Behavioral Rihel et al 2011; Kokel et al 2010
- 12. Types of Libraries • Known function • FDA Approved • Natural product • Privileged library (typically from pharma) • Focused libraries • Focused on class of targets • Focused around a structure
- 13. Common Commercial Libraries • 10,000 DiverSet-Exp – $9,600 for 25uL at 10mM • Sigma LOPAC 1280 compounds – $22,400 for 250uL at 10mM • Prestwick Chemical Library 1280 approved drugs – $10,000 for 100uL at 10mM • Selleck Natural Product Library 753 compounds – $7,775 for 100uL at 10mM
- 14. Exercise 1: Plan a screen Go to the website below and fill out the worksheet: https://goo.gl/forms/oncfqZsHxhbcoT6X2
- 15. Things to note • Timing is critical • Plan how you are keeping your data • Standardize
- 16. Desirable qualities in Hits • Interesting – Novel structure/Novel mechanism of action • Availability/ Synthesizability • Modularity • Solubility • Stability – Avoid highly reactive moieties, unless you want them • Activity window – (x30-x100 lower than lethal concentration
- 17. Reactive Moieties • Reactive compounds • More off target effect • Are metabolized faster • Can be covalent binders • Specific covalent modifiers • Long lived effect • Low concentrations in blood • Unique selectivity • Built in biomarker
- 18. What does prioritizing hits look like? • Cluster compounds to find highly active families • Identify suppliers • Purchase 5mg – 5mg will typically make ~1mL of 10mM stock to work with • Validate primary assay and confirm with secondary assays – Once activity is validated: NMR/ Mass spec • Secondary synthesis with small group of family members – Find activity cliff • Investigate the biology
- 19. Exercise 2: Hit clustering Go to the website below retrieve a list of compounds: https://paper.dropbox.com/doc/Workshop-compound- list-bLhtjY0e5CTbyPLbTb4GQ?_tk=share_copylink These are 40 CID designations for Pubchem.
- 20. Copy the list of IDs
- 21. Exercise 2: Hit clustering • Go to pubchem: https://pubchem.ncbi.nlm.nih.gov/
- 23. 2D VS 3D clustering Note 2 “families” VS 4 “families”
- 24. So you’ve selected a class of molecules to follow, now what?
- 25. Exercise 3: Identify Vendors • In pubchem type: 5389451 • This is a molecule from one of the compound families from before.
- 26. Any and all approaches for target deconvolution: NO SILVER BULLETS Known Target Affinity approach Phenotypic similarity Hild et al 1999 Informatics
- 27. Exercise 4: Cheminformatics • Copy the canonical SMILES CC1=CC=C(C=C1)C2=CC(N3C(=N2)N=CN3)C4=CC=C(C=C4)OC Go to http://www.chemspider.com
- 28. Good indication it might be a kinase inhibitor.
- 29. Resources Cheminformatics • https://www.sciencedirect.com/science/article/pii/S13596 44613001992 Favorite Compound Supplier • https://www.hit2lead.com/ Chemical Phenomics Initiative • Our open source chemotype-phenotype database to facilitate use and accelerate developmet of small molecule tools
- 30. Panel/Questions