eugm15 - stephen pickett (glaxosmithkline): development of web-based chemistry design tools at...

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

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Page 1: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

Development of web-based Chemistry Design Tools at GlaxoSmithKline

Stephen PickettMay 20th, 2015ChemAxon UGM, Budapest

Page 2: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

The Discovery Process

gene protein

targetscreen and

identify lead

Lead

optimisation

chemical

diversity

(compound

library)

test safety& efficacy

in animals and

humans

Targets Hits Leads Candidates Drugs Products

Page 3: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

Drug discovery and computational design and prediction

Target

Selection

Candidate

Selection

Product

Differentiation

Market

Entry

Target IDLead

DiscoveryLead

Optimisation

Preclinical

Development POCFull

DevelopmentRegistration

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

Page 4: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

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

Page 5: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

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

Page 6: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

Simple set up

CornerShops

Target A

Search Corporate Data

Select Assays

Or suggest by project/target

Page 7: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

Email alerting service

Configurable data refresh intervals

Launch of data into excel

or Spotfire templates

Compound property tracking

Project Data Management - CornerShops

Page 8: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

Project Data Management – Structure Viewers

Crystallography data and

comments

Cornershop data

Prealigned view

GRID and other map

views

Electron

density

Page 9: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

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 2.20

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

Page 10: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

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

Occu

pie

d C

ells

CONSTRAINED

UNCONSTRAINED

SELECT

Div

ersi

ty

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.

Page 11: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

QSAR modelling and deployment – expert to end user (JCAMD, 2013, 27, 321-336)

Published Model available as WS

Page 12: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

Our vision:From this….

Page 13: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

To this…

GREAT look and feel

No compromiseScience

Evolving scienceCSC plug-ins

Replace & retireAdept, Adamantis, CSC web apps

Robust

High PerformancePersonalisediDesign

ConfigurableiDesign Fragments

CollaborativeIdeas 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, Intuitive2D, 3D, data, visuals

Page 14: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

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

Page 15: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

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

Page 16: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

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

Page 17: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

LiveDesign Architecture

5/22/2015 17

Page 18: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

Live Reports – The core of the platform

5/22/2015 18

Page 19: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

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On demand properties

Sketch, search, import, enumerate

Page 20: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

205/22/2015

Predefined templates

Sketch, search, import, enumerate

Page 21: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

215/22/2015

Predefined templates

Sketch, search, import, enumerate

Collaboration

Page 22: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

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Predefined templates

Sketch, search, import, enumerate

Collaboration

Design and analysis

Models and computational tools

Protein data and experimental results

Advanced tools

Page 23: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

Collaborative and 3D features

23

Page 24: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

Enumeration

Page 25: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

Multi-pose support

5/22/2015 25

Page 26: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

Model Management

Page 27: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

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 HighlightsP450 Site of Metabolism

Multi-Parameter Optimization

Model Versioning

Atomic Contribution Mapping

Page 28: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

Benefits

5/22/2015 28

• Reduce cycle times for lead optimization

• Unlock users

• EfficiencyUnified 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

Page 29: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

Challenges!!!

5/22/2015 29

• Niche workflows

• Customized tools established

Heterogeneous end user groups

in a global organization

• Worldwide access

• Security

• BugsPerformance

• Co-existing software

• Browsers and plug-insCompatibility

Page 30: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

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

Page 31: EUGM15 - Stephen Pickett (GlaxoSmithKline): Development of web-based Chemistry Design Tools at GlaxoSmithKline

315/22/2015

THANK YOU