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New approaches to elucidating Structure Activity Relationships

Chris Petersen Technical Manager, Informatics. New approaches to elucidating Structure Activity Relationships. Who am I? . Programmer. previously : Distance Learning Performance Management Customer Relationship Management Streaming Video. currently : Kalypsys

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New approaches to elucidating Structure Activity Relationships

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  1. Chris PetersenTechnical Manager, Informatics New approaches to elucidating Structure Activity Relationships

  2. Who am I? • Programmer previously: Distance Learning Performance Management Customer Relationship Management Streaming Video currently: Kalypsys System Architect of Knet, a custom scientific data management system

  3. Who are our end users? • Biologists need to know what compounds are active against a target using a variety of assays • Chemists need to know what are the structural features of compounds that are active for that targetacross a variety of assays

  4. What do the users need from us? Biologists need to know what compounds are active against a target using a variety of assays Chemists need to know what are the structural features of compounds that are active for that targetacross a variety of assays • need to know what compounds are active against a target using a variety of assays • need to know what are the structural features of compounds that are active for that targetacross a variety of assays

  5. How do users need this information displayed? SAR table activity structures

  6. But how is the data for the SAR table selected? SAR table activity structures

  7. But how is the data for the SAR table selected? • Biologists may not know all of the targets the compound is affecting SAR table activity structures

  8. But how is the data for the SAR table selected? • Chemists may not know of active structures unrelated to compound Biologists may not know all of the targets the compound is affecting SAR table activity structures

  9. But how is the data for the SAR table selected? • Chemists may not know of active structures unrelated to compound Biologists may not know all of the targets the compound is affecting <speculation X=“incomplete" Y=“incomplete"> SAR table activity structures

  10. Our goal: develop a new way of displaying SAR data • Give biologists all activities for a compound • all all activity

  11. Our goal: develop a new way of displaying SAR data • Give biologists all activities for a compound • Give chemists all compounds with active structural elements activity all structures

  12. New features of Knet activity targets • Chemoprints • aggregate biological data by target • Biologists can discover off target activity

  13. New features of Knet structural features activity • Chemoprints • aggregate biological data by target • Biologists can discover off target activity • HierS Scaffold • aggregates assay data by scaffolds • Chemists can quickly discover active features • of compounds activity targets

  14. Chemoprints aggregate the activities of compounds activity (efficacy +/- SD) targets (cellular and biochemical) Compound Rosiglitazone (Avandia) Target Chemoprint

  15. Our database structure enables useful aggregation Target Experiment Protocol Experiments are instances of a protocol and all protocols have a defined target All data is generated for a compound in an experiment Each compound gets one number for efficacy and one for potency

  16. Chemoprints aggregate the activities of compounds activity (efficacy +/- SD) targets (cellular and biochemical) Compound Rosiglitazone (Avandia) Target Chemoprint

  17. Example: Rosiglitazone • Rosiglitazone binds to and activates the target, PPAR PPAR

  18. Chemoprints aggregate the activities of compounds by target PPAR (cellular and biochemical) Compound Rosiglitazone (Avandia) Target Chemoprint activity (efficacy +/- SD) targets

  19. Chemoprints aggregate the activities of compounds by target EGR1 (cellular assays) Compound Rosiglitazone (Avandia) • Chemoprint display revealed that PPAR agonists inhibit EGR1 in certain cellular assays Target Chemoprint PPAR (cellular and biochemical) activity (efficacy +/- SD) targets

  20. Aggregating the activity of compounds by target reveals unexpected activities to biologists Kim et al. Toxicological Sciences, 2005 FuDagger et al. J. Biol. Chem., Vol. 277, Issue 30 2002 Compound Rosiglitazone (Avandia) • literature analysis confirmed that PPAR agonists inhibit EGR1 pathway Target Chemoprint PPAR (cellular and biochemical) activity (efficacy +/- SD) EGR1 (cellular assays) targets Chemoprint display revealed that PPAR agonists inhibit EGR1 in certain cellular assays

  21. Target Chemoprints allow biologists to access compound activities in individual experiments Compound Rosiglitazone (Avandia) Target Chemoprint PPAR (cellular and biochemical) activity (efficacy +/- SD) EGR1 (cellular assays) targets

  22. Protocol Chemoprints display compound activities in individual experimental protocols activity (efficacy +/- SD) experimental protocols Compound Rosiglitazone (Avandia) • From this page you can: • access protocol details • explore SAR data Target Chemoprint view off-target activities Protocol Chemoprint

  23. Protocol Chemoprints allow users to access data of active structural elements Compound Rosiglitazone (Avandia) Target Chemoprint view off-target activities Protocol Chemoprint activity (efficacy +/- SD) experimental protocols

  24. Protocol Chemoprints display data of active structural elements Compound Rosiglitazone (Avandia) Target Chemoprint view off-target activities view by experiments Protocol Chemoprint Protocol Detail structural elements (scaffolds) activity

  25. Chemoprints allow navigation to SAR tableof active scaffolds Compound Rosiglitazone (Avandia) • this path allows the SAR data displayed to consider off-target activities and similar structures Target Chemoprint view off-target activities view by experiments Protocol Chemoprint Protocol Detail view by structural elements Standard SAR table compounds (with common scaffold) activity

  26. New features of Knet • Chemoprints • aggregate structural data by assay • Biologists can discover off target activity activity targets

  27. New features of Knet • Chemoprints • aggregate structural data by assay • Biologists can discover off target activity • HierS Scaffold • aggregates assay data by scaffolds • Chemists can quickly discover active features • of compounds activity targets structural features activity

  28. We use HierS scaffold analysis algorithm to classify structural elements in the database 1. identify ring systems ring systems share internal bonds

  29. We use HierS scaffold analysis algorithm to classify structural elements in the database X X identify ring systems trim chains atoms double bonded to linkers and rings are retained chains are atoms and bonds that are external to rings

  30. We use HierS scaffold analysis algorithm to classify structural elements in the database benzenes are ignored identify ring systems trim chains identify basis scaffolds

  31. We use HierS scaffold analysis algorithm to classify structural elements in the database identify ring systems trim chains identify basis scaffolds identify scaffold pairs

  32. We use HierS scaffold analysis algorithm to classify structural elements in the database identify ring systems trim chains identify basis scaffolds identify scaffold pairs add ring systems until original scaffold is reached

  33. We use HierS scaffold analysis algorithm to classify structural elements in the database BIRB794 • the HierS algorithm for BIRB794 results in 9 scaffolds from the original compound

  34. Protocol Chemoprints display data of active structural elements • active scaffolds are selected based on: • multiple rings • >50% efficacy • (all molecules) structural elements (scaffolds) increasing CV activity Compound Rosiglitazone (Avandia) • explore how a structural element is active against a particular target Target Chemoprint view off-target activities view by experiments Protocol Chemoprint Protocol Detail

  35. We use HierS scaffold analysis algorithm to classify structural elements in the database Protocol Detail Scaffold Detail structural elements (scaffolds)

  36. Scaffolds identified by HierS allow navigation to activity information Scaffold Detail Structure Detail structural elements (scaffolds)

  37. Scaffolds identified by HierS allow navigation to activity information structural elements (scaffolds) activity Structure Detail view by scaffold Scaffold Detail

  38. Scaffold Target chemoprints show aggregate data for all compounds that contain scaffold Structure Detail view by scaffold Scaffold Detail view by activity Scaffold Chemoprint aggregate activity data for 34 compounds containing this scaffold

  39. Scaffold Target chemoprints can highlight activity intrinsic to a scaffold Activity not tightly tied to scaffold Structure Detail view by scaffold Scaffold Detail view by activity Scaffold Chemoprint aggregate activity data for 34 compounds containing this scaffold

  40. Scaffold Target chemoprints can highlight activity intrinsic to a scaffold Activity very tightly tied to scaffold Structure Detail view by scaffold Scaffold Detail view by activity Scaffold Chemoprint Activity not tightly tied to scaffold aggregate activity data for 34 compounds containing this scaffold

  41. Summary Chemoprints provide a way for Biologiststo visualize massive amounts of biological data to discover what compounds are active against a target HierS scaffolds provide a means for Chemists to discover what structural features are related to activity and to find distinct scaffold that exhibit that activity

  42. Where I see the future going • R Group Deconvolution could provide insight into why certain compounds containing a scaffold are active while others are not • Activity Searching would allow chemists and biologists to find compounds that exhibit more complex activity than simple activity against one target

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