csilla csank drug...cambridgesoft’s chemdraw 8.0 renderer and drawing tool ©2004 millennium...
TRANSCRIPT
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
©2004 Millennium Pharmaceuticals, Inc. CSANK/Spotfire-Accord 10/25/2004 4
General Usage Information (100 users)
Decision Site Package Usage
FuncGenLeadDiscGeneral
General Decision
Site
Data Source
CustomExportDatabase
File
File
©2004 Millennium Pharmaceuticals, Inc. CSANK/Spotfire-Accord 10/25/2004 5
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
©2004 Millennium Pharmaceuticals, Inc. CSANK/Spotfire-Accord 10/25/2004 6
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
©2004 Millennium Pharmaceuticals, Inc. 10/25/2004 7
Business Needs: Spotfire Integration Projects
©2004 Millennium Pharmaceuticals, Inc. CSANK/Spotfire-Accord 10/25/2004 8
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
©2004 Millennium Pharmaceuticals, Inc. CSANK/Spotfire-Accord 10/25/2004 9
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
©2004 Millennium Pharmaceuticals, Inc. 10/25/2004 10
Cheminformatics Solutions•Integrating Spotfire with Internal Tools that Access Accord Data•Integration of Spotfire directly with Accord Chemistry Cartridge
©2004 Millennium Pharmaceuticals, Inc. CSANK/Spotfire-Accord 10/25/2004 11
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
©2004 Millennium Pharmaceuticals, Inc. 10/25/2004 12
Integrating Spotfire with Internal Tools that Access Accord Data
Export of aggregated and organized project data from “My Drug Discovery” to Spotfire
©2004 Millennium Pharmaceuticals, Inc. CSANK/Spotfire-Accord 10/25/2004 13
Project Team Hub: MDD Project Centric Views
In vitro PotencyAnd Selectivity
PhysicochemicalProperties
PK
Drug Metabolism
and Tox
CompoundStructure
Lot
©2004 Millennium Pharmaceuticals, Inc. CSANK/Spotfire-Accord 10/25/2004 14
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)
©2004 Millennium Pharmaceuticals, Inc. CSANK/Spotfire-Accord 10/25/2004 15
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
©2004 Millennium Pharmaceuticals, Inc. CSANK/Spotfire-Accord 10/25/2004 16
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
©2004 Millennium Pharmaceuticals, Inc. CSANK/Spotfire-Accord 10/25/2004 17
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
©2004 Millennium Pharmaceuticals, Inc. CSANK/Spotfire-Accord 10/25/2004 18
MDL ISIS
MDD Project Views
SpotfireTM for Large Data Set Visualization and
analysis
Pipeline PilotTM WebSpecialized
Queries
Accelrys DS Accord(Corporate database)
©2004 Millennium Pharmaceuticals, Inc. CSANK/Spotfire-Accord 10/25/2004 19
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
©2004 Millennium Pharmaceuticals, Inc. CSANK/Spotfire-Accord 10/25/2004 20
Spotfire: ISIS Structure Analytics
The Prototype
©2004 Millennium Pharmaceuticals, Inc. CSANK/Spotfire-Accord 10/25/2004 21
Spotfire: Accord Structure Analytics
The End Product
©2004 Millennium Pharmaceuticals, Inc. CSANK/Spotfire-Accord 10/25/2004 22
Structure Connection Configuration
• Connect to Database- Choose identifier
©2004 Millennium Pharmaceuticals, Inc. CSANK/Spotfire-Accord 10/25/2004 23
©2004 Millennium Pharmaceuticals, Inc. CSANK/Spotfire-Accord 10/25/2004 24
Structure Viewer
• Click on Structure viewer to see structures
©2004 Millennium Pharmaceuticals, Inc. CSANK/Spotfire-Accord 10/25/2004 25
Mouse over to see structure in structure viewer
©2004 Millennium Pharmaceuticals, Inc. CSANK/Spotfire-Accord 10/25/2004 26
Structures in Table
• See Structures and Data side by side
©2004 Millennium Pharmaceuticals, Inc. CSANK/Spotfire-Accord 10/25/2004 27
Table Viewer with Structures from Accord
©2004 Millennium Pharmaceuticals, Inc. 10/25/2004 28
Accord Structure Searching
©2004 Millennium Pharmaceuticals, Inc. CSANK/Spotfire-Accord 10/25/2004 29
Structure Searching with Accord Cartridge: Substructure, Tanimoto Similarity, and Exact
CambridgeSoft’s ChemDraw 8.0 Renderer and drawing tool
©2004 Millennium Pharmaceuticals, Inc. CSANK/Spotfire-Accord 10/25/2004 30
Edit Structure with Chemdraw Pro Search Window
Copy structure and paste into Structure Search Window
©2004 Millennium Pharmaceuticals, Inc. CSANK/Spotfire-Accord 10/25/2004 31
Search Entire Database or Search within a Spotfire Report
©2004 Millennium Pharmaceuticals, Inc. CSANK/Spotfire-Accord 10/25/2004 32
Similarity Score
ID’s
See Similarity Score
©2004 Millennium Pharmaceuticals, Inc. CSANK/Spotfire-Accord 10/25/2004 33
Similarity Score
ID’s
Order Compounds by Score in Table Viewer
©2004 Millennium Pharmaceuticals, Inc. CSANK/Spotfire-Accord 10/25/2004 34
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
©2004 Millennium Pharmaceuticals, Inc. CSANK/Spotfire-Accord 10/25/2004 35
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
©2004 Millennium Pharmaceuticals, Inc. 10/25/2004 36
Breakthrough science. Breakthrough medicine.SM