Pre-clinical drug discovery strategies include target-based and phenotypic screening, natural substance modifications and biologic approaches. To demonstrate how cheminformatics approaches contributed to the discovery of new medicines we analysed recently approved drugs. In this presentations, we place ChemAxon’s Discovery toolkit in this context and demonstrate possible applications for 2D and 3D similarity studies, high-throughput pairwise molecular alignments or scaffold hopping. Moreover, we also discuss the technological challenges and realization of such applications in corporate platforms.

1. Recent Successful Discovery Strategies:
a ChemoInformatist’s Perspective
Miklós J Szabó, Tímea Polgár

2. Ingenuity
or
Serendipity?

3. Successful Discovery Strategies
pre-clinical research - 1999-2008: 259 agents approved by FDA
Efficacy assesment
ADME profiling
Toxicology/safety
Pharmaceutics
Nature Reviews Drug Discovery 10, 507-519 2011

4. Discovery Toolkit
Screen Suite JKlustor
Discovery Toolkit of ChemAxon
Ligand-based
design
Library designScaffold hopping
Fragment-based
approaches
Lead
optimization
Clustering
Property
prediction
Lead discovery
Metabolism
prediction
Reactor Fragmenter
Calculator
plugins
Metabolizer
Analogue search 3D Alignment Screen3D

5. How to Measure Similarity ?

6. Screen Suite: Screen3D
Flexible – Flexible
alignment
Rigid – Flexible
alignment

7. Benchmark Studies on DUD Dataset
Venkatraman et. al. J. Chem. Inf. Model. 2010, 50, 2079–2093

8. 3D Alignment supported by MCS
• User driven development in collaboration with Eli Lilly
• Rigid-Flexible alignment - new MCS algorithm utilized

9. Another Example for 3D Alignment
Pheniramine & Azatadine
Flexible – Flexible
alignment

10. Use Cases: Scaffold Exchange
H. Sun et al. Drug Discov Today 2012 (7-8) 310-24

11. Screen Suite and JKlustor Integration
JChem Base
JChem
Cartridge
Knime
Pipeline Pilot
Inforsense
Instant JChemJChem for Excel
Desktop
Desktop &
local DB
Enterprise
DB & Oracle
Workflow
tools

12. Self-describing API
Descriptors:
• 2D fingerprints
• 3D shape descriptors
Metrics:
• Tanimoto
• Manhattan
• Tversky
• Euclidean

13. Molecule Profiling by Descriptor and Property Comparison
New Web-based GUI Prototype
Molecule list management:
Store and manage
your screening compounds
MyList
Tabular
display
File manager
Parallel coordinates and
various charts
to visualize complex data
in human readable format
On YouTube: Screen GUI sneak peek

14. Molecule Profiling by Descriptor and Property Comparison
New Web-based GUI Prototype

15. Summary
• Provide integrated solutions
• Focus on user driven development
• Evaluators are welcome
• Let’s meet at Test Lab corner

16. Acknowledgement
Gábor Imre
László Antal
Adrián Kalászi