in partnership with

Making the discoveries that defeat cancer

On the Origins of Three-Dimensionality in Drug-Like Molecules Dr Nathan Brown Group Leader, In Silico Medicinal Chemistry Cancer Research UK Cancer Therapeutics Unit Division of Cancer Therapeutics The Institute of Cancer Research, London

Chemical Computing Group Conference, Vienna, Austria, 2016 Thursday 19th May, 2016 @nathanbroon

Overview 2

• Motivations for enhanced three-dimensionality

• Descriptors of three-dimensionality

• PMI: Principal Moments of Inertia

• PBF: Plane of Best Fit

• Three-dimensionality analyses of drug-like space

• Extant drug-like molecules

• ‘Retrosynthetic’ analyses

• Fragmentation analyses

• Virtual libraries

Structural Moieties Promoting 3D 3

Quaternary Centres

Bridged Bicycles

Conformational Restriction

Spiro Ring Systems

Effexor XR (Venlafaxine)

$1,431 Million (19th) ANTIDEPRESS. & MOOD STAB.

Avapro (Irbesartan)

$370 Million (91st) ANGIOTEN-II ANTAG, PLAIN

Spiriva (Tiotropium)

$1,594 Million (14th) ANTICHOLINERGIC+B2-STIM

Zetia (Ezetimibe)

$986 Million (31st) CHOLEST.&TRIGLY. REGULATOR

28/12/1993

30/01/2004

30/09/1997

25/10/2002

Motivation: Three-Dimensional Molecules

• Mimicking natural products

• Natural products frequently incorporate 3D scaffolds

• Improvement in properties

• 3D shape often conveys improved aqueous solubility

• Addressing new and challenging drug targets

• e.g. protein-protein interactions

4

PDB: 3MXF

(+)-JQ1

Escape from Flatland… 5

1. Lovering, F.; Bikker, J.; Humblet, C. Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. J. Med. Chem. 2009, 52, 6752-6756.

PMI: Principal Moments of Inertia 6

NPR1

NP

R2

0.

5

1

0 0.5 1

disc

rod sphere

ChEMBL Drug-Like Small Molecules

Intuitive in Presentation Size Independent

1. Meyers, J.; Carter, M.; Mok, N. Y.; Brown, N. On The Origins of Three-Dimensionality in Drug-Like Molecules. Future Med. Chem. submitted.

PBF: Plane of Best Fit 7

ChEMBL Drug-Like Molecules

0.00

0.25

0.50

0.75

1.00

1.25

1.50

1.75

2.00

Pla

ne

of B

est F

itSimple in Concept Size Dependency

Unbound Descriptor

1. Meyers, J.; Carter, M.; Mok, N. Y.; Brown, N. On The Origins of Three-Dimensionality in Drug-Like Molecules. Future Med. Chem. submitted. 2. Firth, N. C.; Brown, N.; Blagg, J. Plane of Best Fit: A Novel Method to Characterize the Three-Dimensionality of Molecules. J. Chem. Inf. Model. 2012, 52, 2516-

2525.

Plane of Best Fit 8

0Å

1Å

0.16Å 0.27Å

0.64Å

0.80Å 1.06Å

0.40Å

1. Firth, N. C.; Brown, N.; Blagg, J. Plane of Best Fit: A Novel Method to Characterize the Three-Dimensionality of Molecules. J. Chem. Inf. Model. 2012, 52, 2516-2525.

9 PMI & PBF – Perfect Partners

1. Firth, N. C.; Brown, N.; Blagg, J. Plane of Best Fit: A Novel Method to Characterize the Three-Dimensionality of Molecules. J. Chem. Inf. Model. 2012, 52, 2516-2525.

Scaffold Tree Fragmentation 10

Parent Level 3 Level 2 Level 1 2 Level 0

Simple & Intuitive Rules Mimics Chemist Thinking

Systematic Evaluation

1. Schuffenhauer, A.; Ertl, P.; Roggo, S.; Wetzel, S.; Koch, M. A.; Waldmann, H. The Scaffold Tree – Visualization of the Scaffold Universe by Hierarchical Classification. J. Chem. Inf. Model. 2007, 47, 47-58.

2. Langdon, S. R.; Brown, N.; Blagg, J. Scaffold Diversity of Exemplified Medicinal Chemistry Space. J. Chem. Inf. Model. 2012, 51, 2174-2185.

PMI: Scaffold Tree Analysis of ChEMBL Return to Flatland…

11

Level 5 Level 4 Level 3

Level 2 Level 1 Level 0

Medicinal Chemistry Relevant Scaffolds Tend Towards Planarity

1. Meyers, J.; Carter, M.; Mok, N. Y.; Brown, N. On The Origins of Three-Dimensionality in Drug-Like Molecules. Future Med. Chem. submitted.

PBF: Scaffold Tree Analysis of ChEMBL Return to Flatland…

12

1. Meyers, J.; Carter, M.; Mok, N. Y.; Brown, N. On The Origins of Three-Dimensionality in Drug-Like Molecules. Future Med. Chem. submitted.

Parents 8 7 6 5 4 3 2 1 0

Scaffold Tree Levels

0.00

0.25

0.50

0.75

1.00

1.25

1.50

1.75

2.00

Pla

ne

of

Be

st

Fit

Medicinal Chemistry Relevant Scaffolds Tend Towards Planarity

Scaffolds versus ChEMBL Parents 13

A B C D E F G H

Increasing PBF

★ Core scaffold Parent molecules

1. Meyers, J.; Carter, M.; Mok, N. Y.; Brown, N. On The Origins of Three-Dimensionality in Drug-Like Molecules. Future Med. Chem. submitted.

Scaffolds versus ChEMBL Parents 14

A H

★ Core scaffold Parent molecules

1. Meyers, J.; Carter, M.; Mok, N. Y.; Brown, N. On The Origins of Three-Dimensionality in Drug-Like Molecules. Future Med. Chem. submitted.

Modulation of Three-Dimensionality Easier with Planar Scaffolds

Scaffold versus ChEMBL Parent Molecules 15

A B C D E F G H

Increasing PBF Fig 4 PBF distribution from all eight cores in one plot

A B C D E F G H

0.00

0.25

0.50

0.75

1.00

1.25

1.50

Pla

ne

of

Be

st

Fit

Fig 6 PBF distribution from all eight cores in one plot

A B C D E F G H

0.00

0.25

0.50

0.75

1.00

1.25

1.50

Pla

ne

of

Be

st

Fit

More Three-Dimensional Scaffolds Do Not

Necessarily Translate into More Three-Dimensional

Structures

1. Meyers, J.; Carter, M.; Mok, N. Y.; Brown, N. On The Origins of Three-Dimensionality in Drug-Like Molecules. Future Med. Chem. submitted.

SynDiR – Synthetic Disconnection Rules 16

• New retrosynthetic fragmentation scheme published in 2015

1. Firth, N. C.; Atrash, B.; Brown, N.; Blagg, J. MOARF, an Integrated Workflow for Multiobjective Optimization: Implementation, Synthesis, and Biological Evaluation. J. Chem. Inf. Model. 2015, 55, 1169-1180.

Most Substructures Tend Towards Planarity Three-Dimensionality may Originate from Planar Moieties

Actual Occurrence

Unique Occurrence

SynDiR – Synthetic Disconnection Rules 17

Most Substructures Tend Towards Planarity Three-Dimensionality may Originate from Planar Moieties

1. Meyers, J.; Carter, M.; Mok, N. Y.; Brown, N. On The Origins of Three-Dimensionality in Drug-Like Molecules. Future Med. Chem. submitted.

Scaffold versus Enumerated Libraries 18

A B C D E F G H

Increasing PBF

★ Core scaffold Enumerated library

1. Meyers, J.; Carter, M.; Mok, N. Y.; Brown, N. On The Origins of Three-Dimensionality in Drug-Like Molecules. Future Med. Chem. submitted.

Medicinal Chemistry Relevant Scaffolds Tend Towards Planarity

Scaffold versus Enumerated Libraries 19

A B C D E F G H

Increasing PBF

Fig 4 PBF distribution from all eight cores in one plot

A B C D E F G H

0.00

0.25

0.50

0.75

1.00

1.25

1.50

Pla

ne

of

Be

st

Fit

Fig 6 PBF distribution from all eight cores in one plot

A B C D E F G H

0.00

0.25

0.50

0.75

1.00

1.25

1.50

Pla

ne

of

Be

st

Fit

Greater Increase in Three-Dimensionality when Starting from Flatter

Scaffolds…

…but final structures are more 3D!

1. Meyers, J.; Carter, M.; Mok, N. Y.; Brown, N. On The Origins of Three-Dimensionality in Drug-Like Molecules. Future Med. Chem. submitted.

Summary & Conclusions

Presented approaches to analysing three-dimensionality

• Exemplified medicinal chemistry space

• Paring back structures to scaffolds

• Fragmenting into constituent substructures

• Enumerating virtual libraries

When and where can we enrich three-dimensionality?

• Constituent substructures are relatively planar

• Our medicinal chemistry scaffolds are typically flat

• Three-dimensionality can be modulated in design

• We do not need inherent three-dimensionality in scaffolds & groups

20

Acknowledgements 21

Acknowledgements 22

Cancer Research UK Grant No. C309/A8274

In Silico Medicinal Chemistry

• Fabio Broccatelli

• Michael Carter

• Nick Firth

• Teresa Kaserer

• Sarah Langdon

• Josh Meyers

• Yi Mok

• Lewis Vidler

Medicinal Chemistry

• Julian Blagg