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

Tim DudgeonInformatics Matters Ltd

Oxford, UK

Bob BamfordManaged Ventures LLC

California, USA

Chris PalmerKcc Tech Pty Ltd

Queensland, Australia

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

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

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.

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

Technologies employed

LeadMarker™ architecture

Web apps

LeadMarker™ Web application

Java Web Start apps

runLoader structShare

Service tier

Domain tier

Database tier

chemService assayServicesampleService

chemistry schema

Marvin

JChemStandardizer

chemMarker module

assayMarker module

sampleMarker module

SDLoader externalQuery

overlapAnalyser

accountService

JBoss

Oracle 9i Oracle 10g

cpds batches libraries suppliers samples plates assays runs targets results

sample schema assay schema admin schema

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

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

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

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

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

Batches, compounds, solvents and salts

Batch

Original structure

Standardized structure

Compound

Original structure

Standardized structure

New Batch

Batchstandardizer

Compoundstandardizer

Fragmentation

Typical standardizer configs

<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>

<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>

Batch standardizer – remove common solvents

Compound standardizer – common representation

Salts example

B

B

ID Name Parent Type1 LM-000001 1 CPD

ID Name Parent TYPE2 LM-000003, HCl 2 CPD3 LM-000003 2 CPD4 HCl 2 SALT

chemMarker in action

Demonstration….

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

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)

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

structShare in action

Demonstration….

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

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

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

Contributors - Contacts

● 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

● Informatics Matters

– Tim Dudgeon

– Jon North

– Petr Hamernik

– Svata Dedic

– Milos Kleint

6 Venture, Suite 100Irvine, CA 92618 USA

Yew Tree Farm, High StreetCharlton on OtmoorKidlington, Oxon OX5 2UQ

2 Alpha AvenueCurrumbin 4223Queensland, Australia