JKlustor clustering chemical libraries presented by … maintained by Miklós Vargyas

1. JKlustorclustering chemical librariespresented by …maintained by Miklós Vargyas Last update: 25 March 2010

2. JKlustor Chemical clustering by similarity and structure

3. JKlustor Description of the product JKlustor performs similarity and structure based clustering of compound libraries and focused sets in both hierarchical and non-hierarchical fashion. Availability • part of Jchem • IJC (parts) • server version (accessible via API) • batch application programs • HTML user interface • one desktop application with GUI • GUI is available as an applet

4. Summary of key features Summary of key features • Wide range of methods • Unsupervised, agglomerative clustering • Hierarchical and non-hierarchical methods • Similarity based and structure based techniques • Flexible search options • Tanimoto and Euclidean metrics, weighting • Maximum common substructure identification • chemical property matching including atom type, bond type, hybridization, charge • Interactive display • interactive hierarchy browser (dendrogram viewer) • SAR-table • R-table • Efficient • performance of tools varies between linear and quadratic scale

5. Benefits • Versatile • Choose the most appropriate method to the clustering problem • Combine methods to achieve best results • Use your trusted molecular descriptors in similarity calculation • Easy integration in corporate discovery pipelines • Cluster chemical files directly no need to import structures in database • Intuitive • Cluster formation is self-explanatory

6. Similarity based clustering • Hierarchical • Ward • Non-hierarchical • Sphere exclusion • k-means • Jarvis-Patrick

7. Ward Clustering Features • Ward's minimum variance method results in tight, well separated clusters • Murtagh's reciprocal nearest neighbor (RNN) algorithm to speed it up • quadratic scaling of running time (with respect to number of input structures) • memory consumption scales linearly • best used with smaller sets (like focused libraries), copes with < 100K structures

8. Sphere Exclusion Clustering Features • based on fingerprints and/or other numerical data • running time linear with respect to number of input structures • memory scales sub-linearly • can easily cope with 1Ms of structures • suitable for diverse subset selection

9. k-means Clustering Features • based on fingerprints and/or other numerical data • minimises variance within each clusters • number of clusters can directly be controlled • finds the centre of natural clusters in the input data • running time scales exponentially with respect to number of input structures • can cope with <100Ks of structures

10. Jarp Clustering Features • variable-length Jarvis-Patrick clustering • based on fingerprints and/or other numerical data • takes structures/fingerprint and data values from either files or form database tables • running time scales better than quadratic but worse than linear (with respect to number of input structures) • memory scales linearly • Jarp can cope with 100Ks of structures • depending on data and parameters may create large number of singletons

11. Ward Clustering Example • 8 different sets of know active compounds mixed together • 5-HT3-antagonists • ACE inhibitors • angiotensin 2 antagonists • D2 antagonists • delta antagonists • FTP antagonists • mGluR1 antagonists • thrombin inhibitors • ChemAxon’s 2D Pharmacophore fingerprint was generated • Fingerprints of the mixture were clustered by Ward • 9 clusters were formed • 8 centroids (cluster representative element) corresponded to the 8 activity classes • 1 was a singleton • All 8 real clusters contained structures only from the activity class of the centroid (over 95% true positive classification)

12. Ward Clustering Example Centroids

13. Ward Clustering Example Cluster of the D2 antagonists

14. Structure based clustering • Non-hierarchical • Bemis-Mucko frameworks • Hierarchical • LibraryMCS

15. Bemis-Murcko frameworks

16. Bemis-Murcko frameworks

17. Bemis-Murcko frameworks features • based on structure of molecules • cluster formation is apparent, visual, meets human expectations • running time linear with respect to number of input structures • memory scales sub-linearly • can easily cope with 1Ms of structures • suitable for quick overview of very large sets • spots scaffold hops

18. LibraryMCS Identifies the largest subgraph shared by several molecular structures

19. LibraryMCS: Hierarchical MCS

20. SAR table view

21. R-group decomposition

22. LibraryMCS features • based on structure of molecules • cluster formation is apparent, visual, meets human expectations • running time near-linear with respect to number of input structures • can cope with 100K-200K of structures • suitable for very thorough analysis • spots scaffold hops • substituent-activity (property analysis)

23. LibraryMCS integration at Abbott “Clustering for the masses…”, presented by Derek Debe at ChemAxon’s US UGM, Boston, 2008

24. Clustering performance comparison

25. Jklustor roadmap • In the development pipeline • Bemis-Murcko generalisations • IJC integration • KNIME integartion • New GUI • Manual clustering • Multiple class membership • Disconnected MCS (MOS) • Planned • PipelinePilot integration • Spotfire integration • JChemBase, JChemCartridge integration • JC4XLS integration • Blue sky • Multitouch gestures • LibraryMCS for 1M compound libraries