Novel Approaches to Elucidating Structure Activity Relationships
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Novel Approaches to Elucidating Structure Activity Relationships

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This is a presentation I gave at the San Diego Bioinformatics Forum on October of 2006.

This is a presentation I gave at the San Diego Bioinformatics Forum on October of 2006.

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Novel Approaches to Elucidating Structure Activity Relationships Presentation Transcript

  • 1. New approaches to elucidating Structure Activity Relationships Chris Petersen Technical Manager, Informatics
  • 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 target across a variety of assays
  • 4. What do the users need from us?
    • 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 target across a variety of assays
    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 target across a variety of assays
  • 5. How do users need this information displayed? structures activity SAR table
  • 6. But how is the data for the SAR table selected? structures activity SAR table
  • 7. But how is the data for the SAR table selected?
    • Biologists may not know all of the targets the compound is affecting
    structures activity SAR table
  • 8. But how is the data for the SAR table selected?
    • Chemists may not know of active structures unrelated to compound
    structures activity SAR table Biologists may not know all of the targets the compound is affecting
  • 9. But how is the data for the SAR table selected?
    • Chemists may not know of active structures unrelated to compound
    structures activity SAR table Biologists may not know all of the targets the compound is affecting <speculation X=“incomplete&quot; Y=“incomplete&quot;>
  • 10. Our goal: develop a new way of displaying SAR data
    • Give biologists all activities for a compound
    • all
    activity all
  • 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 structures all
  • 12. New features of Knet
    • Chemoprints
    • aggregate biological data by target
    • Biologists can discover off target activity
    activity targets
  • 13. New features of Knet
    • 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 structural features activity
  • 14. Chemoprints aggregate the activities of compounds Target Chemoprint Compound Rosiglitazone (Avandia) activity (efficacy +/- SD) targets (cellular and biochemical)
  • 15. Our database structure enables useful aggregation 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 Target Experiment Protocol
  • 16. Chemoprints aggregate the activities of compounds Target Chemoprint Compound Rosiglitazone (Avandia) activity (efficacy +/- SD) targets (cellular and biochemical)
  • 17. Example: Rosiglitazone
    • Rosiglitazone binds to and activates the target, PPAR 
    PPAR 
  • 18. Chemoprints aggregate the activities of compounds by target activity (efficacy +/- SD) targets Target Chemoprint Compound Rosiglitazone (Avandia) PPAR  (cellular and biochemical)
  • 19. Chemoprints aggregate the activities of compounds by target
    • Chemoprint display revealed that PPAR  agonists inhibit EGR1 in certain cellular assays
    activity (efficacy +/- SD) targets PPAR  (cellular and biochemical) Target Chemoprint Compound Rosiglitazone (Avandia) EGR1 (cellular assays)
  • 20. Aggregating the activity of compounds by target reveals unexpected activities to biologists
    • literature analysis confirmed that PPAR  agonists inhibit EGR1 pathway
    Chemoprint display revealed that PPAR  agonists inhibit EGR1 in certain cellular assays activity (efficacy +/- SD) targets PPAR  (cellular and biochemical) Target Chemoprint EGR1 (cellular assays) Compound Rosiglitazone (Avandia) Kim et al. Toxicological Sciences, 2005 FuDagger et al. J. Biol. Chem., Vol. 277, Issue 30 2002
  • 21. Target Chemoprints allow biologists to access compound activities in individual experiments activity (efficacy +/- SD) targets EGR1 (cellular assays) PPAR  (cellular and biochemical) Target Chemoprint Compound Rosiglitazone (Avandia)
  • 22. Protocol Chemoprints display compound activities in individual experimental protocols
    • From this page you can :
    • access protocol details
    • explore SAR data
    Target Chemoprint Compound Rosiglitazone (Avandia) view off-target activities Protocol Chemoprint experimental protocols activity (efficacy +/- SD)
  • 23. Protocol Chemoprints allow users to access data of active structural elements Protocol Chemoprint activity (efficacy +/- SD) experimental protocols Target Chemoprint Compound Rosiglitazone (Avandia) view off-target activities
  • 24. Protocol Chemoprints display data of active structural elements Protocol Detail structural elements (scaffolds) Protocol Chemoprint Target Chemoprint Compound Rosiglitazone (Avandia) view off-target activities view by experiments activity
  • 25. Chemoprints allow navigation to SAR table of active scaffolds
    • this path allows the SAR data displayed to consider off-target activities and similar structures
    Protocol Detail Protocol Chemoprint Target Chemoprint Compound Rosiglitazone (Avandia) Standard SAR table view off-target activities view by experiments view by structural elements compounds (with common scaffold) activity
  • 26. New features of Knet
    • Chemoprints
    • aggregate structural data by assay
    • Biologists can discover off target activity
    targets activity
  • 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
    structural features activity activity targets
  • 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
    • identify ring systems
    • trim chains
    chains are atoms and bonds that are external to rings atoms double bonded to linkers and rings are retained X X
  • 30. We use HierS scaffold analysis algorithm to classify structural elements in the database
    • identify ring systems
    • trim chains
    • identify basis scaffolds
    benzenes are ignored
  • 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
    • the HierS algorithm for BIRB794 results in 9 scaffolds from the original compound
    BIRB794
  • 34. Protocol Chemoprints display data of active structural elements
    • explore how a structural element is active against a particular target
    Protocol Detail Protocol Chemoprint Target Chemoprint Compound Rosiglitazone (Avandia) view off-target activities view by experiments structural elements (scaffolds) activity increasing CV
    • active scaffolds are selected based on:
    • multiple rings
    • >50% efficacy
    • (all molecules)
  • 35. We use HierS scaffold analysis algorithm to classify structural elements in the database Scaffold Detail structural elements (scaffolds) Protocol Detail
  • 36. Scaffolds identified by HierS allow navigation to activity information Structure Detail structural elements (scaffolds) Scaffold Detail
  • 37. Scaffolds identified by HierS allow navigation to activity information Scaffold Detail Structure Detail view by scaffold structural elements (scaffolds) activity
  • 38. Scaffold Target chemoprints show aggregate data for all compounds that contain scaffold view by activity Scaffold Detail Structure Detail view by scaffold Scaffold Chemoprint aggregate activity data for 34 compounds containing this scaffold
  • 39. Scaffold Target chemoprints can highlight activity intrinsic to a scaffold view by activity Scaffold Detail Structure Detail view by scaffold Scaffold Chemoprint aggregate activity data for 34 compounds containing this scaffold Activity not tightly tied to scaffold
  • 40. Scaffold Target chemoprints can highlight activity intrinsic to a scaffold view by activity Scaffold Detail Structure Detail view by scaffold Scaffold Chemoprint Activity not tightly tied to scaffold aggregate activity data for 34 compounds containing this scaffold Activity very tightly tied to scaffold
  • 41. Summary Chemoprints provide a way for Biologists to 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