zartler acs fall2015

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


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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A Brief History of FBHG

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1981 1986 1991 1996 2001 2006 2011

DG°AB = DGiA + DGi

B+ DGs


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.


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

http://www.slideshare.net/EdwardZartler/zartler-chi-fbddapr2013

http://www.slideshare.net/EdwardZartler/zing-zartler-jul2014

www.quantumtessera.com 7

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”


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.


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


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

How Many to Put in?

17From http://practicalfragments.blogspot.com


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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Spectra with ASV

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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

zartler acs fall2015

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