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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