Csilla Csank Drug...CambridgeSoft’s ChemDraw 8.0 Renderer and drawing tool ©2004 Millennium...

Csilla CsankSr. Informatics Analyst

Enabling Drug Discovery Project Data Analysis in Spotfirethrough integration with the Accelrys DS Accord Chemistry CartridgeSpotfire User Group MeetingBostonOctober 18-20, 2004© 2004 Millennium Pharmaceuticals Inc.

©2004 Millennium Pharmaceuticals, Inc. CSANK/Spotfire-Accord 10/25/2004 2

Agenda

• Spotfire Use at Millennium • Business Needs: Spotfire Integration

Projects• Enabling Drug Discovery Project Data

Analysis with Spotfire

©2004 Millennium Pharmaceuticals, Inc. 10/25/2004 3

Spotfire Use at Millennium•General Usage Information•Spotfire use across Drug Discovery•Spotfire use in other focus areas


General Usage Information (100 users)

Decision Site Package Usage

FuncGenLeadDiscGeneral

General Decision

Site

Data Source

CustomExportDatabase

File

File


Spotfire Use across Drug Discovery

Chemistry and Biology• Comp Chem models• Virtual Screening• Structure Activity

Relationships• Assay Data

Correlations • Phys chem• DMPK

High Throughput • Data Trends• HTS QC• Screening plates• Combi Chem Library

Results• Trouble Shooting


Spotfire Use in other focus areas

Clinical and Products– Portfolio analysis– Business data-

pharmacovigilence/safety – Product safety– Clinical operational safety

data-outliersOperational

– Budget/portfolio data– metrics/staffing

decisions/resource allocation

Func Genomics– Affy data population

genomics and QC– TxP data– Special algorithms– data-browsing– Pathway data

Molecular Pathology– slide based work-data

reduction


Business Needs: Spotfire Integration Projects


Business Need: Tools for Clinical Data Analysis

• Product Safety Data: Spotfire Signaling Tool to detect early signals of adverse events in patient population.

• Clinical Trial Data: Graphical representation of Clinical Operations Data


Business Needs: R&D

• Chromosomal tool: Visual representation of chromosomal amplifications and deletions in cancer samples using transcriptional profiling data.

• Cheminformatics Solutions: Examine correlations in assay results (in vitro versus cell based or in vivo data for example), probe structure activity relationships: Accord Integration


Cheminformatics Solutions•Integrating Spotfire with Internal Tools that Access Accord Data•Integration of Spotfire directly with Accord Chemistry Cartridge


What’s in our Accord Database?Why is access to

itso important to

Millennium?Accord for Excel Enterprise

Bioassay;Analytical Chem;

PKChemistry

Accord Enterprise

CH3

CH3

DS Accord Corporate database

HTS;Complex BioAssay

Activity Base Templates

ActivityBase

MS Word and MS Powerpoint

Links to Complex DataSOP’s


Integrating Spotfire with Internal Tools that Access Accord Data

Export of aggregated and organized project data from “My Drug Discovery” to Spotfire


Project Team Hub: MDD Project Centric Views

In vitro PotencyAnd Selectivity

PhysicochemicalProperties

PK

Drug Metabolism

and Tox

CompoundStructure

Lot


Business rules

• Geometric Mean for Dose Response• Average or discrete points• Compound average or Lot average• Filter values with operators from mean (<

5, 1, 3 returns 2)• Averaging at distinct concentrations or

doses (e.g AUC@5 mg/kg’ %INH@2uM)


Can I find trends and correlations?Export to Spotfire from My Drug Discovery

MDD Table Exported as XML FileStructures visible but not searchable in Spotfire


Pot

ency

Ki

Toxicity Herg Ki

Desired outcome could be: compounds 10 fold more potent against target receptor than against Herg ion channel

Not toxic,not potent


Pot

ency

Ki

Toxicity Herg Ki

Desired outcome could be: compounds 10 fold more potent against target receptor than against Herg ion channel

>10 X more potent against target


MDL ISIS

MDD Project Views

SpotfireTM for Large Data Set Visualization and

analysis

Pipeline PilotTM WebSpecialized

Queries

Accelrys DS Accord(Corporate database)


To Streamline Process: Direct Access to structures in Accord database by Integration with Accord Cartridge• Model: Spotfire ISIS Structure Analytics

– Table View– Mark records to View structure– Similarity/Substructure Search– List search


Spotfire: ISIS Structure Analytics

The Prototype


Spotfire: Accord Structure Analytics

The End Product


Structure Connection Configuration

• Connect to Database- Choose identifier


Structure Viewer

• Click on Structure viewer to see structures


Mouse over to see structure in structure viewer


Structures in Table

• See Structures and Data side by side


Table Viewer with Structures from Accord


Accord Structure Searching


Structure Searching with Accord Cartridge: Substructure, Tanimoto Similarity, and Exact

CambridgeSoft’s ChemDraw 8.0 Renderer and drawing tool


Edit Structure with Chemdraw Pro Search Window

Copy structure and paste into Structure Search Window


Search Entire Database or Search within a Spotfire Report


Similarity Score

ID’s

See Similarity Score


Similarity Score

ID’s

Order Compounds by Score in Table Viewer


The business issue

Spotfire approach The results

Featured Products• DecisionSite• Lead Discovery• Functional

Genomics• Developer

Application Areas• Chemistry• Biology• Screening• Safety• Clinical• Project Data• Bioinformaitcs

In order to abrogate the need to transfer structures from Accord to ISIS for use with Spotfire, and as part of a project to provide researchers with integrated tools accessing our corporate database, we initiated a project with Spotfire to build an Accord Structure Analytics set of tools.

• Provide Key Professional Services to work on defined data integration projects at Millennium

• Build Accord Structure Analytics Tools based on the ISIS Structure Analytics prototype

• Leverage the power of Accelrys’ Accord Chemistry Cartridge

• Work with Millennium’s staff to display Accord data and perform fast and reliable structure searching capabilities with the Accelrys’ Accord Chemistry Cartridge

• Simplified approach to access chemistry data from corporate database

• Streamlines Millennium’s Cheminformatics platform and reduce maintenance of structural data in two databases reducing overhead and cost

• permit chemists to analyze large datasets and take advantage of the Power of Spotfire Visualization

• Will extend to a separate database for high-throughput chemistry soon to be upgraded to Accord

Spotfire at Millennium Pharmaceuticals


Acknowledgements

• Tricia Vos and Mike Patane for MC4 project data– Marsilje et al.,2004, Bioorganix & Medicinal

Chemistry Letters in press– Vos et al., 2004, J. Med. Chem. 47: 1602-1604

• David Sedlock; Sagar Shah; Ed Frees; Paul Greenspan; Peter Strack; Greg Tucker-Kellogg; Ben Knight; John Graham; Christian Reich; Thomas Scarnecchia

• Spotfire: Kevin Hannigan, Mark Salisbury, Greg Miller, Don Sullivan, Chaim Indig


Breakthrough science. Breakthrough medicine.SM

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