At GSK we have a long history of putting design & analysis tools into the hands of medicinal chemists. However, for a variety of reasons, we have found ourselves with a proliferation of tools available. Few of these tools integrate well with other systems, still fewer give a positive user experience, and feedback from our chemists is that it is difficult to know what they all do, and which to use when. For the computational scientists, the centrally supported systems were inflexible and difficult to keep current, whilst any new tool required re-implementation of input-output and visualisation components. We decided to remedy the situation by using a commercially supported product which could provide the core system, one with a modern look & feel which would encourage chemists to use design tools, collaborate with each other on those designs, and which could also provide a “plug and play” environment for computational scientists. This talk will describe the journey that led us to the choice of Schrodinger’s LiveDesign system, highlight the ChemAxon components that enable some of the core functionality and provide examples of how the system can be used collaboratively within a program team.

1. Development of web-based
Chemistry Design Tools at
GlaxoSmithKline
Stephen Pickett
May 20th, 2015
ChemAxon UGM, Budapest

2. The Discovery Process
gene protein
target
screen and
identify lead
Lead
optimisation
chemical
diversity
(compound
library)
test safety& efficacy
in animals and
humans
Targets Hits Leads Candidates Drugs Products

3. Drug discovery and computational design and prediction
Target
Selection
Candidate
Selection
Product
Differentiation
Market
Entry
Target ID
Lead
Discovery
Lead
Optimisation
Preclinical
Development POC
Full
Development
Registration
Predictive ADMET
Structural Genomics
Sequence homology
Molecular Diversity
Library Design
Molecular Similarity
HTS analysis
(Q)SAR analysis
Attrition analysis/risk assessment
Structure Based Design
Ligand based Design
Solid state/multi scale modelling

4. Drug discovery made simple
Corporate
collection
Screen
Analysis
What to
make next?
Make it
What’s here to begin
with? What should we
add?
Primary target assay
Selectivity assays
Developability screens
Disease models
“Decision support”
Clustering
Machine learning
Visualisation
Are we there yet?
Predictive models
Design algorithms

5. Current State: tools covering many application areas
• Data access and reporting
• SAR analysis and visualisation
• Reagent selection and enumeration
• Similarity, clustering, focussed sets
• Alignment and pharmacophore generation
• Protein/ligand visualisation and interpretation
• QSAR modelling
–Local and global models
• Docking, scoring, idea prioritisation
55/22/2015
New compound design

6. Simple set up
CornerShops
Target A
Search Corporate Data
Select Assays
Or suggest by project/target

7. Email alerting service
Configurable data refresh intervals
Launch of data into excel
or Spotfire templates
Compound property tracking
Project Data Management - CornerShops

8. Project Data Management – Structure Viewers
Crystallography data and
comments
Cornershop data
Prealigned view
GRID and other map
views
Electron
density

9. BioDig ADME (Hussain, Rea, JCIM, 2010, 50, 339-348)
“What possible changes could be made to the
compound to improve its clearance ?
Binned ACTIVITY_CHANGE
1
2
3
5
4
17
21
7
2
-2.2 -1.8 -1.4 -1 -0.6 -0.2 0.2 0.6 1 1.4 1.8 2.2
0
5
10
15
20
PROFILE_CLUSTER - 22
PROFILE_CLUSTER - 28
PROFILE_CLUSTER - 33
PROFILE_CLUSTER - 23
PROFILE_CLUSTER - 31
PROFILE_CLUSTER - 34
PROFILE_CLUSTER - 27
PROFILE_CLUSTER - 32
PROFILE_CLUSTER - 38
- - - 0 + + + - - - 0 + + + - - - 0 + + +
0
10
20
30
40
50
60
70
80
90
100
0
10
20
30
40
50
60
70
80
90
100
0
10
20
30
40
50
60
70
80
90
100
Matched Molecular Pairs analysis in compound design

10. State of the art design in global tools
MW HBD RB HBA CELL SIZE
0
100
200
300
400
0 192 384 576 768 960 1152 1344 1536
Library Size
OccupiedCells
CONSTRAINED
UNCONSTRAINED
SELECT
Diversity
Library Size
T. Wright, V. J. Gillet, D.V.S. Green & S.D. Pickett, Optimizing the Size and Configuration of
Combinatorial Libraries. J. Chem. Inf. Comput. Sci. (2003), 43(2), 381-390.

11. QSAR modelling and deployment – expert to end user (JCAMD, 2013, 27, 321-336)
Published Model available as WS

12. Our vision:
From this….

13. To this…
GREAT look and feel
No compromise
Science
Evolving science
CSC plug-ins
Replace & retire
Adept, Adamantis, CSC web apps
Robust
High Performance
Personalised
iDesign
Configurable
iDesign Fragments
Collaborative
Ideas sharing
Target IC50 IC50 AVG IC50
Target1 1.99 -1.84 0.08
Target2 2.50 -0.10 1.20
Target3 1.81 4.62 3.22
Target4 5.91 2.59 4.25
Target5 4.15 4.52 4.34
Target6 4.22 4.58 4.40
Target7 4.34 4.49 4.41
Target8 5.11 4.50 4.80
Target9 6.31 5.40 5.86
Target10 5.37 6.47 5.92
Target11 6.48 7.22 6.85
Target12 8.43 9.19 8.81
Target13 9.31 11.07 10.19
Target14 11.89 11.72 11.81
Target15 10.88 14.74 12.81
Target16 11.53 14.31 12.92
Target17 12.62 13.25 12.93
Target18 14.58 13.36 13.97
Target19 13.34 15.34 14.34
Target20 14.13 15.23 14.68
MW 451 fSP3 0.21
cLogP 4.1 TPSA 77
HBD 1 HBA 3
SKETCH
ENUMERATE
DOCK
PLOT
IMPORT
Integrated, Intuitive
2D, 3D, data, visuals

14. The concept originated from our desire to improve efficiency,
increase compound quality, and reduce attrition
Efficiency
• Drug design
• Selection of
chemistry targets
Quality
• Physico-chemical
properties
• PK/Safety
Success
• Reduce attrition
• Patient benefit

15. How to achieve our goals: what do our chemists want and need?
• 12 Workshops
– 4 R&D sites
– ~100 chemists
• Open session at the GSK Chemistry Conference (including our CEO!)
• Pan R&D Survey
– Who designs molecules?
– How?
5/22/2015 15

16. What is LiveDesign?
• A design tool for small molecule medicinal & computational chemists
– Drawing, importing, enumerating structures
– Calculating properties
– Searching structure databases
– Import of measured data
– Visualisation of data & structures
– Generation & visualisation of 3D conformers
– Visualisation of Protein structures
– Collaboration environment
– Project based views & preferences
– Ability to add new calculations & workflows
– Advanced functionality (…see later)
• Consolidation of many existing tools into a single platform, replacing those that
are outdated or unsustainable

17. LiveDesign Architecture
5/22/2015 17

18. Live Reports – The core of the platform
5/22/2015 18

19. 195/22/2015
On demand properties
Sketch, search, import, enumerate

20. 205/22/2015
Predefined templates
Sketch, search, import, enumerate

21. 215/22/2015
Predefined templates
Sketch, search, import, enumerate
Collaboration

22. 225/22/2015
Predefined templates
Sketch, search, import, enumerate
Collaboration
Design and analysis
Models and computational tools
Protein data and experimental results
Advanced tools

23. Collaborative and 3D features
23

24. Enumeration

25. Multi-pose support
5/22/2015 25

26. Model Management

27. More features being developed and integrated……
• Many more…….Prioritization needed by the chemistry community over the next 1-2 months
5/22/2015 27
Binding Interaction Highlights
P450 Site of Metabolism
Multi-Parameter Optimization
Model Versioning
Atomic Contribution Mapping

28. Benefits
5/22/2015 28
• Reduce cycle times for lead optimization
• Unlock users
• Efficiency
Unified platform
• Get peer review and team feedback on both
virtual and synthesized compounds
• Share ideas and contribute to projects across
GSK
Collaborative
environment
• Time and cost savings
• The cost of losing a compound after Candidate
Selection estimated as £6M
Simplification

29. Challenges!!!
5/22/2015 29
• Niche workflows
• Customized tools established
Heterogeneous
end user groups
in a global
organization
• Worldwide access
• Security
• Bugs
Performance
• Co-existing software
• Browsers and plug-ins
Compatibility

30. Key factors to success
5/22/2015 30
• Speed similar or better than
existing tools
• Smooth - not “buggy”
Performance
• Appealing interface
• Quality renderingLook and Feel
• Easy to use
• Minimal trainingIntuitive
• GSK-Schrödinger
• End users
• Shape the final release
Communication
Get it right
Happy chemists!
High user uptake

31. 315/22/2015
THANK YOU