VAMOS Visualization of Accessible Molecular Space A new compound filtering and selection interface Spotfire User Conference - Europe - May , 2003 Jens Schamberger, Graffinity Pharmaceuticals AG

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 Chemical Microarrays Affinity Fingerprints Data Mining SPR Imaging Parallel Chemistry Molecular Modeling Medicinal Chemistry

4608 Individual Compounds per SPR Image Monomer 1 Monomer 2 Compound Acquisition Fragments for chemical microarrays Monomers for combinatorial chemistry Reagents for lead optimization

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 DB Company Inventory ? Need for database merging External Databases Individual Hviews Limited Annotation Company Inventory Well curated Virtual Databases Typical questions Overlap Similarity

Selection Criteria Range of Molecular Properties Molweight, clogP H-Don, H-Acc, Rot.Bonds Presence/ Absence of Functional Groups Amines, Acids... MedChem ‘badgroups’ Protecting Groups Presence/ Absence of Substructures/Pharmacophores privileged structures known scaffolds Need for compound annotation

Filtering Procedures Hard Filters Individual Selection Criteria e.g. : e.g. “at least one primary amine and molecular weight 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 DATA BASE Filter Subset List Need for flexible filtering tools

Rules and Profiles Need for dynamic selection tools 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

Flexible filtering tools Dynamic selection tools Compound Selection from Databases Supplier consolidation Database merging Compound annotation Typical „ spotfire what-iffing “ VAMOS Perl

VAMOS Overview MDL Isis Databases Oracle Modelling and Cheminformatics Data Storage

VAMOS: Merging of Database ACD NBB ESC IRC A Available C Chemicals D Directory N New B Building B Blocks E External S Screening C Compounds I In-house R Registered C Chemicals ISIS Databases Graffinity Unified Chemical DB MDL Reagent Selector Isis DB with > 600,000 unique cmpds complete source tracking easily expandable by additional databases

TRIPOS Unity DB VAMOS: Linking with Cheminformatics Oracle VAMOS DB Modelling & Cheminformatic Tools Extract Molecular Data Perl DBI Graffinity Unified Chemical DB Store Molecular Annotations

Standard Properties Identifiers ACD number, NewBB ID, ChemID,... Supplier Information Ranking, „Best Supplier“,... „Lipinski-Like“ Properties MW, ClogP, Don, Acc, Rings, Nrot,... Rule Based Features Andrews Energy,... Presence of Functional Groups COOH, -NH2, -NH-, Customized Properties Presence of Special Substructures privileged fragments, bad groups,.... Cell Based Similarity BCUT-Space, Substructure Classes, SOM Affinity Information „Hit on Array“ easily expandible ISIS Database +Oracle DB / Tab-Separated-Value File ________________________________ = Customizable Molecular Spreadsheet „one row one structure“ „one column one property“ VAMOS: Storing Molecular Annotations

VAMOS: Flowchart ACD NBB ESC IRC GUCD Pharmacophore and Substructure Query Definition (XML) Create Guide HTML Oracle VAMOS DB Create/update Initiate queries Get query results Store query results SGI Oracle Server New New Queries Cron Job TRIPOS Unity DB

VAMOS: Spotfire Guide

ACD Collected Catalogues In - house : colored Source Database

good very good reasonable unreliable Supplier- Ranking

Similarity / Self Organizing Map

Donor - Acceptor Distribution

Profile Plot (Rule of Five)

Conclusions 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 VAMOS : Visualization of Accessible Molecular Space

Acknowledgement : Dr. Günther Metz Dr. Dirk Tomandl Helmut Wittneben Graffinity Pharmaceuticals AG