Zartler Zing FBDD Jul2014
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Fragonomics The –omics that will have real impact?
Edward R. Zartler, Ph.D
Quantum Tessera Consulting
The Silk Road
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Central Asian Cultures
The –omics Revolution
• Genomics
• Chemogenomics
• Metabo*ics
• Genochenomics
• Proteomics
• Toxicogenomics
• Transcriptomics
• Fragonomics
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Fragonomics
• Sample More “Chemical Space”
• Better Chance of Finding Starting Point
• All MedChem is Deliberate and Efficient
• Highly Integrated Process
5 Zartler and Shapiro (2005) Curr. Opin. Chem. Biol., 9:366.
Fragments are Ubiquitous
• (Almost) every Big Pharma has FBHG integrated into their process
• Smaller companies are doing it.
• Institutes are doing it.
• Academics are doing it
• Birds are doing it, bees are doing it.
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Fragonomics Comes in Many Flavors
• Anabolic
– Find the active, build it up
– Find the active -> Analog by Catalog/Collection
• Catabolic
– Fast follower, patent busting
• Multiple Binding
– Synergy
The Empires of the Silk Road, 3rd Century
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Parthians
Persians
Xiongnu
Kushans Han
The Pieces are Interchangeable
• Libraries
• Screening
• Prosecution is the Key
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The Pieces are Interchangeable Libraries
• Libraries
– Big
– Small
– Diverse
– Biased
– 2D
– 3D
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Library Selection
• Choice of approach affects choice of library
Anabolic Catabolic
known inhibitor
Biased Diverse
Novel Lead
N
Me Too
Y
PK
Y
Betterment N
Multiple
First Binder
Diverse N
Biased
Y
Y
N
Second Fragment
From 2002
2D vs. 3D Fragments
• Is this an either/or proposition? – Shouldn’t be…like anything its compromise
• The ideal library would be: – Primarily 2D fragments (very planar) “Chemical Space”
– Large enough to cover sufficient chemistry space
– No need for Built-in SAR (sufficent readily accessible follow up)
– Portion of 3D fragments, but related to the 2D members “Vector Space”
– Rapidly accessible follow up fragments for SAR
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How to Get More 3D-arity
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OH
H
H
H
OH
H
H
H
HH
Bicyclo(1.1.1)pentane -> Phenyl isostere Meanwell (2011) J. Med. Chem. 54, 2529.
3D Isosteres
The Empires of the Silk Road, 13th Century
• Primary Screen
– Direct Binding Best
– NMR (best for PPI), very information rich
• Secondary Screen
– At least one orthogonal binding method
– Indirect methods are check boxes
What information would you make a decision on?
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The Pieces are Interchangeable Screening
Indirect vs. Direct Methods
• Indirect Methods (Biochem., TS, ITC, MS, etc.)
– False negatives, False Negatives, False Negatives
• Direct Methods (NMR/SPR/Native-MS)
– NMR: Native solution conditions
– SPR: Immobilized Protein/Target
– Native-MS: Must Fly
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The Pieces are Interchangeable Screening
• SPR
– But what do off-rates mean?
– What’s a slow off mean?
• NMR
– Super-duper-Awesome, but resource INTENSIVE
– Structural Information in the Absence of Structure
– Protein QC as you go
• Native Mass Spec
– Enthalpy only binding
– Protein QC as you go
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It’s a question of resources and will.
• Active -> Hit
– Analog by Catalog/Collection
– Structure is great, but NOT required
– Biophysical characterization
– Medchemist not required.
• Hit Confirmation
– MedChemist required?
• Structure
– Is it necessary?
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The Pieces are Interchangeable Prosecution
What are the Known Unknowns?
Do you understand it well enough to make a decision from it?
• Kinetics
• Thermodynamics
– Enthalpically driven binding…
– Entropy leads to chaos?
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The Empires of the Silk Road, 15th Century
Ottomans
Persians
Mongols
Kushans Ming
Europe
The Future is Now?
• Design principles have been completely co-opted
• It is the age of the Biophysicist
• Non-structurally enabled targets?
– Intrinsically Disordered Proteins
– Membrane proteins
• Multi-Protein Complexes
• Is anything unligandable?
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The Future is Now?
• Time to revisit the Past?
– RAMPED-UP NMR
– Ligand Immobilized SPR
– What else?
• Internecine warfare
– Sound and fury or real war?
• Is there one (as a separate field)?
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