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VAMOS
Visualization of Accessible Molecular Space
A new compound filtering and selection interface
Spotfire User Conference - Europe - May 20 - 21, 2003
Jens Schamberger, Graffinity Pharmaceuticals AG
www.graffinity.com
About Graffinity
•
Technology-driven drug discovery
and pre-clinical development company
•
Founded 1998
•
Headquartered in Heidelberg
Germany
•
~ 90 people
•
Funding to date 41 M Euro
Technology
•
Proprietary Screening Platform
• Chemical Microarrays
• Label-free Surface Plasmon Resonance Imaging
•
Evolutionary Drug Discovery Strategy (RAISE®)
• Rapid Affinity Informed Structural Evolution
Integrated
Discovery
Platform
Parallel
Chemistry
Molecular Modeling
Medicinal Chemistry
Affinity Fingerprints
Data Mining
Chemical Microarrays
SPR Imaging
•
Fragments for
chemical microarrays
•
Monomers for
combinatorial chemistry
•
Reagents
for lead optimization
Monomer 2
Compound Acquisition
4608 Individual Compounds per SPR Image
Monomer 1
Distributed Supplier Information
•
Individual Vendors
• Printed Catalogues
• SD-Files
• Databases
•
Online Databases
•
Compiled Collections
• Available Chemical Directory (MDL)
• Chemicals Available for Purchase (Accelrys)
•
Virtual Collections
Need for supplier consolidation
Database Consistency & Integration
•
External Databases
• Individual Hviews
• Limited Annotation
•
Company
Inventory
External DB
Company Inventory
• Well curated
•
Virtual Databases
•
Typical questions
• Overlap
• Similarity
Need for database merging
?
NO2
Selection Criteria
•
Range of Molecular Properties
Cl
HOOC
• Molweight, clogP
• H-Don, H-Acc, Rot.Bonds
N
N
•
Presence/ Absence of Functional Groups
• Amines, Acids ...
• MedChem ‘badgroups’
• Protecting Groups
•
O
O
Presence/ Absence of Substructures/Pharmacophores
• privileged structures
• known scaffolds
Need for compound annotation
Filtering Procedures
•
Hard Filters
DATA
BASE
• Individual Selection Criteria e.g. :
•
•
•
•
•
•
e.g. “at least one primary amine
and molecular weight 100 - 300 Da
and clogP smaller 5
and number of halogens smaller 4
Even Lipinski criteria often taken as
hard filter while it was meant as a rule
No step back using hard filters
Need for flexible filtering tools
Filter
Subset
List
Rules and Profiles
•
Soft Description with
Case by Case Decisions
•
Rules
• Allowance for limited violation of criteria
• e.g. “no more than one Lipinski violation”
• Definition of own rules
•
Profiles
• Subsets based on defined property profiles
• Compound similarity based on common profile
Need for dynamic selection tools
Compound Selection from Databases
Supplier consolidation
Flexible filtering tools
Database merging
Dynamic selection tools
Compound annotation
Perl
Typical „spotfire what-iffing“
VAMOS
VAMOS Overview
MDL Isis
Databases
Modelling and
Cheminformatics
O
O
Data Storage
HOOC
N
N
Oracle
NO2
Cl
VAMOS: Merging of Database
ISIS Databases
Available
Chemicals
Directory
New
Building
Blocks
External
Screening
Compounds
In-house
Registered
Chemicals
MDL Reagent Selector
ACD
NBB
ESC
Graffinity
Unified Chemical DB
IRC
• Isis DB with > 600,000 unique cmpds
• complete source tracking
• easily expandable by additional databases
VAMOS: Linking with Cheminformatics
Perl DBI
Graffinity
Unified Chemical Extract
Molecular
DB
Data
Store
Molecular
Annotations
Modelling &
Cheminformatic
Tools
TRIPOS
Unity DB
Oracle
VAMOS
DB
VAMOS: Storing Molecular Annotations
O
O
HOOC
+
N
N
=
NO2
Cl
ISIS Database
Oracle DB / Tab-Separated-Value File
________________________________
Customizable Molecular Spreadsheet
„one row one structure“
„one column one property“
Standard Properties
Customized Properties
•
•
Identifiers
•
•
Supplier Information
•
•
MW, ClogP, Don, Acc, Rings, Nrot,...
Presence of Special Substructures
•
•
Cell Based Similarity
•
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privileged fragments, bad groups, ....
BCUT-Space, Substructure Classes, SOM
Affinity Information
•
„Hit on Array“
Rule Based Features
•
•
Ranking, „Best Supplier“, ...
„Lipinski-Like“ Properties
•
•
ACD number, NewBB ID, ChemID,...
Andrews Energy, ...
Presence of Functional Groups
•
COOH, -NH2, -NH-, ......
•
easily expandible
N
VAMOS: Flowchart
SGI
ACD
NBB
Pharmacophore and
Substructure Query
Definition (XML)
Create/update
GUCD
ESC
Initiate queries
Get query results
Cron Job
Store query results
IRC
New
New Queries
Create Guide
HTML
Oracle
Server
Oracle
VAMOS
DB
TRIPOS
Unity DB
VAMOS: Spotfire Guide
Source Database
ACD
In - house : colored
Collected
Catalogues
Supplier- Ranking
very good
good
reasonable
unreliable
Similarity / Self Organizing Map
Donor - Acceptor Distribution
Profile Plot (Rule of Five)
Conclusions
VAMOS : Visualization of Accessible Molecular Space
• Integrated view across databases
• Extensive compound annotations
• Dynamic selection & real-time filtering capabilities
• Adjustable to specific compound acquisition needs
• Expandable for profiling of virtual libraries
• Adaptable for analysis of screening data
Acknowledgement :
Dr. Günther Metz
Dr. Dirk Tomandl
Helmut Wittneben
Graffinity Pharmaceuticals AG