Many medicinal chemistry relevant structures and core scaffolds tend towards geometric planarity. However, structural planarity may preclude the optimisation of physicochemical properties desirable in drug-like molecules, such as solubility. Furthermore, as new and challenging drug targets, such as protein-protein interactions, become more prevalent in drug design projects, the inherent potential to exploit three-dimensionality of chemical structures in lead optimisation is increasingly important. To this end, there has been recent interest in designing molecular fragments for fragment screening and subsequent derivatisation that exhibit enhanced three-dimensionality [1]. However, it remains unclear the extent to which core scaffolds require enhanced three-dimensionality in order to yield molecular designs with desired three-dimensionality. Here, three computational methods are applied to investigate the emergence of three-dimensionality in drug-like molecules, namely: fragmentation analysis using a recently reported fragmentation algorithm, SynDiR [2]; iterative pruning of pendant substituents using the Scaffold Tree fragmentation rules [3,4]; and the virtual enumeration of drug-like molecules from molecular fragments of varying three-dimensionality. Using the recently published three-dimensionality descriptor Plane of Best Fit (PBF), amongst other descriptors, it is possible to assess the potential three-dimensionality of molecular fragments objectively [5]. The combination of these three approaches to investigate the emergence of three-dimensionality in drug-like molecules informs on the stages at which three-dimensionality should be considered in a drug design project. These methods permit a greater understanding of the properties of the derived functional groups and scaffolds from exemplified medicinal chemistry space and their contributions to three- dimensionality. This study has highlighted key learning that is anticipated to enhance medicinal chemistry design in the future.

1. 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

2. 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

3. 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

4. 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

5. 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.

6. PMI: Principal Moments of Inertia 6
NPR1
NPR20.51
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.

7. 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
PlaneofBestFitSimple 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.

8. 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. 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.

10. 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.

11. 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.

12. 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
PlaneofBestFit
Medicinal Chemistry Relevant Scaffolds Tend Towards Planarity

13. 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.

14. 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

15. 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
PlaneofBestFit
Fig 6 PBF distribution from all eight cores in one plot
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.

16. 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

17. 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.

18. 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

19. Scaffold versus Enumerated Libraries 19
A B C D E F G H
Increasing PBFA B C D E F G H
0.00
0.25
0.50
0.75
1.00
1.25
1.50
PlaneofBestFit
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
PlaneofBestFit
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.

20. 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

21. Acknowledgements 21

22. 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