LeadMarker™ – an integrated suite for managing chemical and biological information

1. LeadMarker™ – an integrated suite for managing chemical and biological information Tim DudgeonInformatics Matters LtdOxford, UKBob BamfordManaged Ventures LLCCalifornia, USAChris PalmerKcc Tech Pty LtdQueensland, Australia

2. About LeadMarker™ • A Modular suite of apps based on Java Enterprise Edition (J2EE) • Management of core chemical and biological data for Life Science companies • Allow deployment of different configurations to different customers • Built around the objects you deal with and the workflows you operate with • Designed around high performance and scaleability

3. LeadMarker™ Features • chemMarker • Chemical registration • Chemical searching • Manages compounds, batches, libraries • sampleMarker • Plate and/or vial sample management • Liquid handling and transformation operations • assayMarker • Manages biological results • Simplified data acquistion from instruments • Data processing to generate biological results • %INH • IC50 • Tabular and graphical reporting

4. LeadMarker Features (2) • structShare • a chemical spreadsheet, including its SDLoader plug-in that facilitates a simple mechanism for library registration into chemMarker. • structShare has the ability to handle over 100,000 structures simultaneously • runLoader • A tool to read raw instrument data files, associate biological data with samples, and store the data in assayMarker. • runLoader requires valid containers, registered via sampleMarker, to associate the data.

5. Goals for LeadMaker • Increase software flexibility by • A single code base from which we can push out multiple “branded versions,” each with its own configuration • A working system that we can support • Not a CD in an envelope • Integration hotspots allowing extension and customisation • Make the scientist's life easy by • LeadMarker™ should correspond to real world objects • Should support scientific workflows • Adaptable • Configurable

6. Technologies employed

7. LeadMarker™ architecture Web apps Java Web Start apps Marvin LeadMarker™ Web application runLoader structShare chemMarker module sampleMarker module assayMarker module SDLoader externalQuery overlapAnalyser JBoss Service tier chemService sampleService assayService accountService Domain tier cpds batches libraries suppliers samples plates assays runs targets results JChem Standardizer Database tier Oracle 9i Oracle 10g chemistry schema sample schema assay schema admin schema

8. Key benefits of ChemAxon to LeadMarker • Single set of Java tools • Designed to work in harmony • All tools have been developed by ChemAxon since their inception • No mergers of other party’s code • Flexibility • Database vendor independence • Molecule format neutral • Configurable components e.g. standardizer • Performance • Support & documentation

9. Marvin Applets in web applications • Use for display and editing structures • Structures • before and after standardization • Sketching of structures • for registration • for searching • onMouseOver previews

10. Use of JChem in LeadMarker • JChem databases for compound and batch structures • Choose not to use cartridge • Allow other dbms vendors • Maximise performance • Keep cost to a minimum • JChem Base provides sufficient functionality • Two stage standardization • Provides highly flexible definition of chemical business rules

11. Salts, stereochemistry and mixtures • Typically this is the biggest headache for a chemical registration system • Problem with standard “salt stripping” approaches • Loss of information and/or data in multiple places • Typically need to define salts up front • Difficult to change your view of what is a salt and what isn’t • Problems with stereochemistry • MDL chiral flag • Absolute and relative stereochemistry • Uncertainty • Symptoms • Changes in rules or data means (biological) data has to be moved around • Database administrators and technical staff are kept busy fixing errors

12. LeadMarker™ approach to salts and mixtures • Register what you have, salts and all • Salts do not get stripped • Compounds that are composite are broken into their parts and their components also registered • Parent child relationships within composite compounds are maintained • A user can flag any component as a salt and name it • No data needs to be relocated

13. Batches, compounds, solvents and salts New Batch Batch Batch standardizer Original structure Standardized structure Compound Original structure Compound standardizer Standardized structure Fragmentation

14. Typical standardizer configs Batch standardizer – remove common solvents <StandardizerConfiguration Version ="0.1"> <Actions> <Reaction ID="Water" Structure="O>>" Exact="true"/> <Reaction ID="DMSO" Structure="CS(C)=O>>" Exact="true"/> <Reaction ID="Methanol" Structure="CO>>" Exact="true"/> <Reaction ID="Acetonitrile" Structure="CC#N>>" Exact="true"/> </Actions> </StandardizerConfiguration> Compound standardizer – common representation <StandardizerConfiguration Version ="0.1"> <Actions> <Aromatize/> <Reaction ID="PlusMinus" Structure="[*+:1][*-:2]>>[*:1]=[*:2]"/> <Reaction ID="PlusMinusDouble" Structure="[*+:1]=[*-:2]>>[*:1]#[*:2]"/> <Reaction ID="nitro" Structure="[O-:2][N+:1]=O>>[O:2]=[N:1]=O"/> <Reaction ID="azide" Structure="N=[N:1]#[N:2]>>N=[N+:1]=[N-:2]"/> <Reaction ID="enamine" Structure="[H:4][N:3][C:1]=[C:2]>>[H:4][C:2][C:1]=[N:3]"/> <Reaction ID="enol" Structure="[H:4][O:3][C:1]=[C:2]>>[H:4][C:2][C:1]=[O:3]"/> <Reaction ID="ammoniumhalide" Structure="[F,Cl,Br,I;-:3].[H:2][N+:1][#6]>>[F,Cl,Br,I:3][H:2].[N:1][#6]"/> <Reaction ID="sulphate" Structure="[C,c:1][S:2](=[O:3])(=[O:4])[O;H1:5]>>[C,c:1][S:2](=[O:3])(=[O:4])[O-:5]"/> <Reaction ID="carboxylate" Structure="[C,c:1][C:2](=[O:3])[O;H1:4]>>[C,c:1][C:2](=[O:3])[O-:4]"/> <ImplH ID="implh" Charged="true" Radical="true" Mapped="true"/> <Sgroups ID="ungroup" Act="Ungroup"/> <Clean ID="cleanIfNeeded"/> </Actions> </StandardizerConfiguration>

15. ID Name Parent TYPE 2 LM-000003, HCl 2 CPD 3 LM-000003 2 CPD 4 HCl 2 SALT Salts example B ID Name Parent Type 1 LM-000001 1 CPD B

16. chemMarker in action • Demonstration….

17. structShare – chemical spreadsheet • Alternative to form builders and office spreadsheets • Neither of these are good solutions • Office software limits performance and scaleability • Installation and support involves • Office suite licensing • Platform specific libraries (windows DLLs) • structShare designed to address this • Large datasets: > 100,000 structures managed easily • Rapid sorting and filtering • Workbench for analysing and processing data • Easy deployment through Java Web Start • Provides workbench for LeadMarker functionality • High volume data input or output • Ability to persist files locally and collaborate informally

18. structShare features • Embedded SQL database • Fast sorting and filtering of large datasets • Manage relational data • Future use of JChem searching • Memory only or disk based modes • SDfile and text file import and export • Plug-in architecture and API allows extension • sdLoader for registering libraries into LeadMarker™ • OverlapAnayzer for identifying structural overlap between your sample structures and what is already registered in LeadMarker™ • ExternalQuery plug-in for querying LeadMarker™ and other SQL databases (under development)

19. Use of ChemAxon tools within structShare • Marvin for molecule rendering • MViewPane used as TableCellRenderer • MarvinSketch as molecule editor • MolImporter/MolExporter for reading/writing SDF • JChem in ovelap analysis - classify according to • exact match • match to unsalted form • no match • Future • use of JChem to allow structure filtering • integration of Chemical Terms • integration of Reactor for library enumeration

20. structShare in action • Demonstration….

21. LeadMarker™ Team • LeadMarker™ has been developed by a global team that provides regional customisation and expertise • Organisation • LeadMarker™ Licensor • North America & Japan – Managed Ventures LLC • Regional Agents • Europe – Informatics Matters Ltd • Australasia – KCC Tech Pty Ltd

22. Consortium History • Managed Ventures Incorporated in 1999 • Initially focused on custom informatics consulting • Syrrx, Kalypsys, Triad, Anadys, Salk Institute, Merck, Medsn • Genomics Institute of Novartis • Eli Lilly and Company • European expansion with Informatics Matters collaboration • Recent expansion into Australasia with Kcc Tech agency • Several custom chemical registration and screening software implementations led to the development of the LeadMarker™ integrated suite • ►To be formally released at World Pharmaceutical Congress in Philadelphia

23. Contributors - Contacts • Informatics Matters • Tim Dudgeon • Jon North • Petr Hamernik • Svata Dedic • Milos Kleint • Managed Ventures • Jack Crawford • Bob Bamford • Nadeem Bitar • Bob Thomas • Chris Novak • Matt Houser • Emma Davila • Brad Ziola • Arthur Clements • KCC Tech Pty • Chris Palmer Yew Tree Farm, High Street Charlton on Otmoor Kidlington, Oxon OX5 2UQ 6 Venture, Suite 100 Irvine, CA 92618 USA 2 Alpha Avenue Currumbin 4223 Queensland, Australia