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Designing Fragment Libraries:Past, Present, and Future
Edward R. Zartler, Ph.D
Quantum Tessera Consulting
&Chemical Equity Group
www.quantumtessera.com
The design of fragment libraries has been the subject of much discussion overthe past 20 years of the field’s existence. Like fine art, everyone who hasdesigned a library has their own opinion of what is beautiful. Through theyears the beauty of fragments has evolved: scaffolds, privilege, the Rule ofThree, 3D vs. flat, super-huge libraries vs. very small, PAINs, focused or not, etc.All fragments are beautiful. As is often said, it’s not how big (or small or flat orwhatever) your fragment is, it’s how you screen it. Orthogonal validation ofscreen actives is crucial. More important than how you use it is how you curateit. This presentation will discuss the state of the art of Fragment Libraries:design, utilization, and curation.
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Abstract
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Acknowledgements
• Chris Swain, Cambridge MedChem
• Maybridge
– Rob Zambias
– Simon Pearce
• Mestrelab
– Chen Peng
– Santi Dominguez
– Carlos Cobas
– Manuel Perez
• Monash
– Martin Scanlon
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Fragonomics
• Cover a significant portion of available chemical space
• Minimize “bad” interactions
• Every atom added to the molecule is wanted
• Rapid Iteration
• No compositional bias in libraries
• Easy to control quality (Solubility, purity, etc.)
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Zartler and Shapiro (2005) Curr. Opin. Chem. Biol., 9:366.
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My Challenge:Or why is a biophysicist speaking to compchemists?
• Libraries have problems:
“Fat, Drunk, and Stupid is No Way to Go through Life”: (Re)Thinking Fragment Libraries
• Where did the problems come from?
You!
• How so? Because you can do great things, but only with rules.
• Fragonomics: the –omics that will have real impact?
6Slides on Slideshare
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Fragment Library Design
Drug Discovery Today (2001) 6:133Four Things are Crucial to a Good Fragment library
1. Large Number of Compounds
2. Very Water Soluble
3. Very Diverse
4. Synthetically Tractable
< 0.1% of Available Compounds
Drug Discovery Today (2003) 8:876Rule of Three
1. MW< 300 (we use Heavy atom count)
2. H-BondDonor< 3, H-BondAcceptor < 3
3. cLOGP< 3
4. # RotBonds< 3, PSA< 60 also suggested
Voldemort Rule
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Higgs-Zartler NMR Fragment Library (2001-2)
Slice MDDR
Query with Results(Internal Collect)
Remove Duplicates
1 ring: < 12HA2 ring: < 16HA
(#HBA>0) or (HBD=0,1,2,3)
1H exists
Atkins Diet(no carbs)
Obviously Bad removal
Relaxed Medchem Rules
Charged molecules, aldehydesNitros removed
> 2 Substitutions removed
No Bridged bicyclics
No geminal substituted Molecules
“Floppy” chains removed
C2-Symmetric Molecules Removed
No Excessively large Substitutions
Zartler Optical Filter (ZOF)
No “too many link atoms between rings”
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State of the Art: Solubility
Experimentally Measure, and first!
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E.R. Zartler et al. (2013) Drug Discovery World, Winter 2012/2013
The Rules Change
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Brewer et al. “Assembling a Fragment Library” (2008)in Fragment-based Drug Discovery: Practical AspectsE.R. Zartler and M.J Shapiro, eds.
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Evolution of FragmentsOntogeny
• Must look like drugs
– Slicing up the MDDR (2001)
– “Drugs in Other Drugs” (Siegal and Vieth, 2007)
• Generic vs. Focused (Schuffenhauer, 2005)
• Natural substrates
– Decode’s Fragments of Life (Davies et al., 2009)
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Evolution of FragmentsSpecies
• Similarity vs. Diversity
• Make the library have nearest neighbors
– Built-in SAR (“What do I do with a single binder?”)
Analog by Catalog
• Diversity Wins
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Evolution of FragmentsCovalency
• Warheads vs. non-reactive (different than PAINS)
• Specificity is key.
– Thiols for MMPs
– Chloroketones for serine proteases
– Good for tools, not for drugs…
• Specificity is NOT key, reactivity is..
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Evolution of Fragment TheoryShape
• Flat vs. shapely
• Vector Space
• 3D Isosteres (Meanwell (2011) J. Med. Chem. 54, 2529)
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fSP3
nPMI
H
H
H
CH3O
H
H
H
H
H
CH3O
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Evolution of Fragment TheoryOntology
• Aromatic vs. aliphatic
• Blame it on NMR
– Avoids buffer component overlap
– Epitope mapping is only good for same class of 1H
– Other methods don’t care
• Astex has shown that flat fragments are “better”
• 19F…all bets are off
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How Big Are Fragments?
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7 HA @ 5mM = 0.30 LEAN10HA@ 1mM= 0.30 LEAN
20HA @ 1mM = 0.30 LEAN16HA@ 16mM= 0.30 LEAN
From http://practicalfragments.blogspot.com
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Proper Curation
• MedChem Rules
• Diversity Rules
• PAINs Removal
• QC– LC-MS
– NMR
– qNMR
• Experimental Solubility (DMSO and aqueous)
• Aggregation via NMR
• CLEAN Screen (for SPR)
• Aqueous Spectra for NMR screening
• Pooling
• Integration with Data Analysis
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Quantum Tessera-Maybridge-Mestrelab
• Maybridge
– >2500 curated fragments with 30,000 more as backup
– Aqueous spectra to facilitate NMR screening
• Mestrelab
– Aqueous spectra and ASV in Mnova DB
– Integrated with ELN and other analytical data
• Quantum Tessera
– Consulting and Service Provider to make it all work
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Missing: not enough ref peaks matched the scout peaks, hence the compound is considered missing from the mixture.
Present: The compound presents, but none of the intensity changes meets the criteria Non-selective hit: At least one of the intensity changes meets the criteria , but has not
passed the competition test (if Protein+Inhibitor spec are used).Specific hit: At least one of the intensity changes meets the criteria , and also passed
the competition test, if any.
Results from Full Automation