GSK is upgrading their small molecule registration system to allow end users to fully specify stereochemistry in molecules without intervention from registrars. This will use the v3000 mol format to accurately represent stereochemistry. However, downstream systems currently rely on v2000 format or standard SMILES, causing inconsistent search results for stereochemistry queries. GSK plans to upgrade databases and services to use v3000 format as the standard to ensure consistent searching across applications by mid-2016. This will also help meet future European legislation requirements for describing medicines.

1. Consistent Stereochemical
search at GSK
Support for v3000 mol format.
Richard Bolton
Stephen Swanson

2. Abstract
2
• GSK has recently upgraded its ChemAxon small molecule registration system to allow
end-users the ability to mark-up and register molecules with complex atom based stereo
centres with no registrar intervention. These are stored using the V3000 mol
format. These more fully described structures will now be pushed to the GSK Chemistry
ODS and indexed using the latest JChem cartridge. This in turn will allow upgrade of
structure query web services and IJC projects to give accurate and consistent behaviour
across IJC clients and other web-service powered structure search tools when running
complex stereo-chemical queries. This presentation will discuss the current issues and
how the move to using v3000 mol format resolves these problems. A timeline will be
shared which shows when GSK will have moved to v3000 mol as its standard for full
representation of small molecules; this solution will also align with the future
requirements of European legislation on fully describing medicinal products.
19 May 2015ChemAxon UGM Budapest

3. Agenda
1. Small molecule registration at GSK. Full atom mark-up and end user
registration checker. A status update.
2. Downstream inconsistency in structure search
3. Plans to use v3000 mol format as GSK’s new standard and how that fixes the
problems.
4. The work that needs doing and the timeline
5. Where next IJC Browser and IDMP.
319 May 2015ChemAxon UGM Budapest

4. Small Molecule Registration. A reminder.
4
• Small Molecule Registration collaboration project with ChemAxon started in
March 2011 and went to production in mid 2012.
• Simplification of small molecule registration
– A-novel-Approach-to- Pharmaceutical-Registration :Charlie Wilkins San Diego 2011
– Going live with registration as a service : Richard Bolton/Akos Papp Budapest 2012
– Registration as a Service: the full story after half a year. Rama Bhamidipati/Akos Papp Boston2012
• End user tools to check registration were rolled out in mid 2014
19 May 2015ChemAxon UGM Budapest

5. Current Registration Process
5
Other?
Compound Name
CCE 001
CCE 002
CCE 003
Purchased
Compounds
Compound Collection Enhancement send the SD File
to Registry as received and registered as new entities
optionally, request
assistance from the
registrar
Contract
Chemist
Chemist
CCE
Chemist
eLNB or
WebReg
Fully Specified compounds
Registrar
Tools
Compound Collection
Enhancement purchase
compounds and receive data files
with structure information
Registrar
SD FilesSD Files
Fully Specified compounds Business Rules
Staging
Compounds that are fully
describe in regard to
stereochemistry, racemic content
are automatically registered
Chemist or contract coordinator
enter compounds to be registered
and registerability before
submitting
Compounds with undefined
attributes are sent to the
registrars
Registrars modify compounds for
consistency, confirm with the
chemist then register
Registry
x
x
x
19 May 2015ChemAxon UGM Budapest

6. Small Molecule registration statistics
6
• Between April 2014 and April 2015
– 175K compounds registered.(end user singleton and bulk registration)
– 50K end user singletons
– 24k with chiral centers
– 9.5k with 2-9 chiral centers
– 700 with >=10 chiral centers (more likely to be peptides or DNA, soon to be go to our new Biological
Registration system)
• So far in 2015
– Singletons autoregistered 78%
– Singletons registered manually by the submitting scientist (non-registrar manual) 8%
– Singletons registered manually by registrars 14%
19 May 2015ChemAxon UGM Budapest

7. Side-effects of full atom mark-up.
7
• Although the Compound registration system now contains full atom mark-up
downstream systems still rely on v2000 mol format copies and/or standard
smiles strings.
• Structures can be overlaid with ‘pictures’ of the mark-up so users can tell
‘identical’ structures apart, but these are not query features.
• Running a query in IJC or using the GSK structure search web service can give
different results for molecules containing relative stereochemistry.
• Scientists agreed that this inconsistency needed to be resolved.
19 May 2015ChemAxon UGM Budapest

8. 8
Examples 1 Generic

9. –
IJC
4917 compounds
Helium
Query Structure
Unspecified
Stereochemistry
4921 compounds
Problem 1: Searching With Unspecified Stereochemistry
9
Note the 4917 compound set may not be a subset of the 4921 found in IJC. It may contain other
structures based upon what is entered. It takes a long time to determine which actually contain what
you were looking for.
19 May 2015ChemAxon UGM Budapest

10. Problem 2: Searching With Specified Stereochemistry
10
–
Helium
IJC
4921 compounds
Query Structure
Specified
Stereochemistry
Returns all the structures
with the unspecified
stereochemistry, not the
specific And1
designations!
If the user is more specific in the search, IJC ignores the input (searches via unspecified
stereochemistry) and Helium just affords an error leaving the scientist unsure of the results.
19 May 2015ChemAxon UGM Budapest

11. Problem 3 Data Integrity
11
Get GSK ID
Get Structure
Helium
This compound number defines a
non-specific structure!
GSK 12345A
GSK 12345A
19 May 2015ChemAxon UGM Budapest

12. Problem 3 Potential Data Integrity converting structure to ID to structure
12
Get GSK ID
Get Structure
Helium
This compound number defines a
non-specific structure!
GSK 12345A
GSK 12345A
Structure X
absolute stereo
Structure Y
relative stereo
19 May 2015ChemAxon UGM Budapest

13. 13
Examples 2 More specific

14. Isomer Synthesis
4 Isomers (R,R, R,S, S,R, S,S)
2 Isomers (R,R, R,S,)
2 Isomers (R,R, S,R,)
A
B
C
19 May 2015ChemAxon UGM Budapest

15. 4 Diasteromers – Registration (A)
Racemic starting materials + Isomer Separation
19 May 2015ChemAxon UGM Budapest

16. 4 Diasteromers – Registration (C)
From (R) Amine + Isomer Separation
From (S) Amine + Isomer Separation
19 May 2015ChemAxon UGM Budapest

17. Substructure Searching Outcomes
Did we make this structure?
Did we include all relevant
structures in the patent?
Is this structure part of
an Alliance agreement?
Can I trust my SSS results?
19 May 2015ChemAxon UGM Budapest

18. Target and proposal
Target
• Ensure consistent and correct search results irrespective of the application being
used.
Proposal
• Cascade the fully described v3000 molfile that is stored in Registry to both IJC
and Chemistry Web Services.
1819 May 2015ChemAxon UGM Budapest

19. What needs changing to achieve this?
 Upgrade CODS and ACD databases from Oracle 10g to Oracle 12c and ensure they contain v3000 mol
and index
 Update JChem Cartridge in Chemistry ODS (CODS) and the Available Chemical Directory (ACD) to enable
full stereo-chemical searching
 Reconfigure IJC to search across and return from the new structure field (ChemAxon provided script)
 Add methods both Structure Search and ID Lookup Web services which search across and return V3000
results.
 Maintain the existing V2000 methods and results to ensure that other downstream applications are not
impacted
 Upgrade Helium v3 to v4 and configure it to search across and return the V3000 results.
 Ensure that Helium and IJC return identical results with identical V3000 queries
 Plan remediation of the other 34 apps dependent on the web services.
1919 May 2015ChemAxon UGM Budapest

20. Timeline
20
May Jun Jul Aug Sep Oct Nov Dec Jan
JChem upgrade in CODS &
ACD
Project Approval Project Release
Helium v4 He 4 + V3000
2
3 Sandbox Dev (TST/INT) Prd
1
4
UKxxx605 Oracle 12c upgrade & testing5
Resolve
Registry Issue
IJC & CL/SS
Migrate Chemistry Webservices
to Java 86
Warranty
Project Close
19 May 2015ChemAxon UGM Budapest

21. What next..............
IDMP requirements
– The full description of all materials in a medicinal product will be required by mid 2016.
– V3000 mol is a format that can fulfil that requirement.
IJC Browser
– ChemAxon are working inside the GSK environment to tune IJC Browser
–Plans to move to Browser this year if performance is acceptable in our complex environment.
2119 May 2015ChemAxon UGM Budapest

22. Thank you for your attention
2219 May 2015ChemAxon UGM Budapest
Questions?