AstraZeneca’s cheminformatics platform for large-scale integration of structure and bioactivity data

1. Chemistry Connect
AstraZeneca’s cheminformatics platform for
large-scale integration of structure and
bioactivity data
ICIC 2012 14-17 October Berlin
Sorel Muresan
AstraZeneca R&D Mölndal
Chemistry Innovation Centre, Discovery Sciences

2. Chemistry Connect – a team effort
Discovery Sciences | CIC
http://dx.doi.org/10.1016/j.drudis.2011.10.005

3. Driver – explosion in SAR data
• Chemical information landscape changing fast
• Make every SAR point count, access all available chemistry
• Internal & external datasources
2006 2008
Discovery Sciences | CIC
Southan, C.; Varkonyi, P.; Muresan, S., J. Cheminfo. 2009

4. SAR key entities and relationships
Unstructured Data Structured Entries in
from Documents Relational Databases
Expert Extraction
or
Text Mining
Discovery Sciences | CIC
Southan, C.; Boppana, K.; Jagarlapudi, S.; Muresan, S. J. Cheminfo. 2011

5. Manually extracted SAR data (commercial)
• GOSTAR (GVKBIO Online Structure Activity Relationship Database) is a
comprehensive database that captures explicit relationships between the three
entities of publications, compounds and targets.
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6. SAR data (public)
• PubChem
• the NCBI public informatics backbone for the NIH Molecular
Libraries Initiative focused on small molecules as systems
biology probes and potential therapeutic agents.
• ChEMBL
• includes drugs, small molecules from the medicinal chemistry
or biochemical literature and their targets.
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7. Extracting chemical entities from text
Collaboration with IBM Research Almaden to apply
text analytics technology to analyze intellectual
property and scientific literature
- 10 million full text patents
- 11 million structures
- 17% out of 58M parent structures in Chemistry Connect
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8. Chemical Named Entity Recognition (NER)
7-CHLORO-1,3-DIHYDRO-1-METHYL-5-
PHENYL-2H-1,4-BENZODIAZEPIN-2-ONE
Name-to-Structure
software
CN1c2ccc(cc2C(=NCC1=O)c3ccccc3)Cl
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9. Extracting chemical entities from text
The biggest cause of missing compounds when extracting
chemical entities from text is the presence of typographical
errors: human errors, OCR failures, hyphenation and
multiple line issues, etc.
• Automated spelling correction with CaffeineFix from
NextMove Software
• CaffeineFix significantly improves extraction rates (22%
increase from D=0 to D=1)
• name2structure software are complementary (40% of the
structures come from single n2s contributions)
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Sayle, R.; Xie, P.; Muresan, S., JCIM 2012

10. Chemistry Connect
Compound
Document
Test & Result
Chemistry Connect
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11. Chemistry Connect
Compound
Document
Test & Result
Target
Chemistry Connect
Discovery Sciences | CIC

12. Chemistry Connect
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13. Chemistry Connect
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14. Chemistry Connect
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15. Exact match source comparisons
sources that include predominantly patent-
known drugs derived compounds
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16. Finding a common language
Acetaminophen
[3H]Acetaminophen 882-720-13 Acetaminophen (4-hydroxyacetanilide)
10066-90-7 882-720-16 Acetaminophen glucuronide(55%)
acetaminophen sulfate
103-90-2 882-720-20 Acetaminophen sulfate(30%)
1047-607-00 A F ANACIN acetaminophen sulphate
Acetaminophen Uniserts
1169-894-12 A PER acetaminophene
A.F. ANACIN Acetamol
16110-10-4 ACETANILIDE, 4'-HYDROXY-
AAP Acetavance
222 AF aa-sulfate Acetofen
222-AF AA-sulphate
ACETOMINOPHEN
Actamin
3-(glutathion-S-yl)acetaminophen Abenol Actamin Extra
Actamin Super
37519-14-5 Abensanil Actifed Plus
3-hydroxyacetaminophen ABROL Actimol
Actimol Chewable Tablets
4-(Acetylamino)phenol ABROLET Actimol Children's Suspension
4-13-00-01091 AC112578 Actimol Infants' Suspension
Actimol Junior Strength Caplets
4-ACETAMIDOPHENOL AC112579 Actron
Acamol Afebrin
4-Acetaminophenol Afebryl
Accu-Tap Aferadol
4-ACETYLAMINOPHENOL Acenol AG10223
4'-Hydroxyacetanilide Acenol (pharmaceutical)
AG12029
AG124687
4-HYDROXYACETANILIDE Acephen AG12800
AG12948
4-HYDROXYANILID KYSELINY OCTOVE Acertol Amadil
4-hydroxyphenolacetamide Aceta Aminofen
644/4046 Aceta Elixir Aminofen Max
Anacin
644/7502 Aceta Tablets Anacin-3
64889-81-2 Acetaco Anacin-3 Extra Strength
Acetagesic Anadin dla dzieci
659/9501 Anaflon
Acetalgin
77097-85-9
Acetaminophen:
Analter
ACETAMIDE, N-(4- Anapap
840-416-00 HYDROXYPHENYL)- Andox
>1000 synonyms.. 872-667-00
878-022-04
ACETAMIDE, N-(P-
HYDROXYPHENYL)-
Anelix
Anexsia
Anexsia 10/660
878-022-09 Acetamidophenol Anexsia 5/325
878-022-14 Acetaminofen Anexsia 7.5/325
Acetaminophen Anexsia 7.5/650
878-022-19 Anhiba
882-720-04 Acetaminophen (4- Anoquan
hydroxyacetanilide) Anti-Algos
882-720-07 Antidol
Acetaminophen
882-720-10 glucuronide(55%)
Apacet
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Apacet Capsules
acetaminophen sulfate

17. Word of the Day : Crowdsourcing
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18. Chemistry Connect
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19. Technical Overview - ETL
Data Sources Extraction Transformation Loading
Text Files Python Structure
Scripts Normalization
(chemistry) Property calc
Oracle PL/SQL
Oracle DB (ext tables)
Pipeline Pilot
(biological results)
Web
Service
Discovery Sciences | CIC

20. Technical Overview - Application
HTML
Java
Oracle 11g WebLogic Server
Direct 7 REST (and SOAP) services
.Net
PipelinePilot
Knime
Excel
Discovery Sciences | CIC

21. Chemistry Connect Apps
Canvas
SARConnect
Chemistry Plato
Connect
Key
compounds
Discovery Sciences | CIC

22. Canvas
is…
…a Rosetta stone for
compounds
It automatically translates AZ numbers, 196 B.C. 2012 A.D.
SNs, chemical names, structures, SMILEs,
development IDs, reagent IDs, trade
names, legacy Astra & Zeneca IDs… …really easy to use
Copy a compound name or
structure to the clipboard and let
…a portal to information Canvas do the rest of the work
It acts as a springboard to let you access
Chemistry Connect, ISAC, IBEX, IBIS data,
Compound View, ELN data, AZ Patent Db, IBEX,
Integrity... …and in 2011, 1750 AZ scientists did
Safety assessment
& many others…
Biologists
Med chem Synthetic chem
…a compound design tool Patent attorneys
It quickly calculates C-lab properties, chemical Crystallographers
names, molecular weights, checks novelty…
DMPK
Comp chem Discovery Sciences | CIC
Jon Winter, Oncology iMed

23. Utopia Documents
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http://getutopia.com/index.php

24. Key compound prediction from patents
From WO1996025405 the earliest patent which claims it, can you
work out the structure of Bextra (Valdecoxib), the Pfizer NSAID?
74 exemplified cmpds
Discovery Sciences | CIC
Tyrchan, C. et al JCIM 2012

25. WO1996025405 - Bextra
Source #compounds Bextra Bextra
exists ranked
GVKBIO 74 Y 1 (broad core)
1 (narrow core)
SureChem 501 Y 1 (broad core)
1 (narrow core)
Discovery Sciences | CIC

26. EP268956 - Aciphex
Source #compounds Aciphex Aciphex
exists ranked
GVKBIO 27 Y 2 (core1)
1 (core2)
SureChem 168 Y 1 (core1)
1 (core2)
Discovery Sciences | CIC

27. PLATO for Safety/Tox – General Concept
Predictive Secondary
Pharmacology
Expert
Systems
QSAR
Models
Job
Input Results
Molecule BioSim
Summary
Pharma
Connect
Additional
Services
Scott Boyer
Catrin Hasselgren
Lars Carlsson All services in Plato are complementary to
Tobias Noeske find an overall answer to your problem!
Discovery Sciences | CIC

28. Predictive Secondary Pharmacology strategy
Chemistry Connect
Similarity or
Compound information: name & structure
substructure search
Target information: bioactivity data
Input
Molecule
Compound - Target associations
• Potential off-target effects?
• Part of a safety risk assessment
Scott Boyer Similarity concept: Similar compounds
Catrin Hasselgren bind to similar targets.
Lars Carlsson M Johnson et al., Prog Clin Biol Res (1989), 291:167
Discovery Sciences | CIC
Tobias Noeske P Willet, Drug Discov Today (2006), 11:1046

29. SARConnect – navigate SAR landscape
Compound hierarchy
Test &
Results
Target hierarchy
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Eriksson, M. et al Molecular Informatics 2012

30. SARConnect – structure classification
Compound structure Molecular Framework Topological Framework Terminal Rings & Bonds
Level 1 Level2 Level 3 Level 4
Discovery Sciences | CIC

31. SARConnect – target classification
Level 1 (Broad target class)
Enzyme NHR GPCR Ion Channel Other
Level 2 (Swiss-Prot family class)
GPCR Signal Transmembrane Transmembrane
Level 3 (Sub-families)
Class A Class B Class C Frizzeled Family
Symbol
CALCR CALCLR CRHR2 GCCR GIPR GLP1R
PTH2R VIPR1 VIPR2
Discovery Sciences | CIC

32. SARConnect – navigate SAR landscape
Discovery Sciences | CIC

33. Take-home messages
• Chemistry Connect is enabling AstraZeneca to intensify its
exploitation of synergies between internal and external SAR estate
and to shorten the time between hypothesis generation during DMTA
cycles
• Our Chemical Dictionary of 120 million chemical terms has become a
crucial cross-mapping resource between chemistry and the scientific
literature
• We cannot wave a magic wand over data quality, provenance issues,
drug name space, and the inherent challenges of chemistry
representation but Chemistry Connect gives us a unique overview and
amelioration options for each source
Discovery Sciences | CIC

34. A Democracy of Ideas (Acknowledgements)
• Plamen Petrov • Niklas Blomberg
• Chris Southan • Jon Winter
• Paul Xie • John Cumming
• Peter Varkonyi • Scott Boyer
• Thierry Kogej • Catrin Hasselgren
• Christian Tyrchan • Lars Carlsson
• Magnus Kjellberg • Tobias Noeske
• Håkan Nilsson • and many others…
• Mats Eriksson
• Jonas Ekengren
• Ithipol Suriyawongkul
Discovery Sciences | CIC

35. Thank you!
Discovery Sciences | CIC