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.

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Novel Approaches to Elucidating Structure Activity Relationships

  1. 1. New approaches to elucidating Structure Activity Relationships Chris Petersen Technical Manager, Informatics
  2. 2. Who am I? <ul><li>Programmer </li></ul>previously : Distance Learning Performance Management Customer Relationship Management Streaming Video currently : Kalypsys System Architect of Knet, a custom scientific data management system
  3. 3. Who are our end users? <ul><li>Biologists need to know what compounds are active against a target using a variety of assays </li></ul><ul><li>Chemists need to know what are the structural features of compounds that are active for that target across a variety of assays </li></ul>
  4. 4. What do the users need from us? <ul><li>need to know what compounds are active against a target using a variety of assays </li></ul><ul><li>need to know what are the structural features of compounds that are active for that target across a variety of assays </li></ul>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. 5. How do users need this information displayed? structures activity SAR table
  6. 6. But how is the data for the SAR table selected? structures activity SAR table
  7. 7. But how is the data for the SAR table selected? <ul><li>Biologists may not know all of the targets the compound is affecting </li></ul>structures activity SAR table
  8. 8. But how is the data for the SAR table selected? <ul><li>Chemists may not know of active structures unrelated to compound </li></ul>structures activity SAR table Biologists may not know all of the targets the compound is affecting
  9. 9. But how is the data for the SAR table selected? <ul><li>Chemists may not know of active structures unrelated to compound </li></ul>structures activity SAR table Biologists may not know all of the targets the compound is affecting <speculation X=“incomplete&quot; Y=“incomplete&quot;>
  10. 10. Our goal: develop a new way of displaying SAR data <ul><li>Give biologists all activities for a compound </li></ul><ul><li>all </li></ul>activity all
  11. 11. Our goal: develop a new way of displaying SAR data <ul><li>Give biologists all activities for a compound </li></ul><ul><li>Give chemists all compounds with active structural elements </li></ul>activity structures all
  12. 12. New features of Knet <ul><li>Chemoprints </li></ul><ul><li>aggregate biological data by target </li></ul><ul><li>Biologists can discover off target activity </li></ul>activity targets
  13. 13. New features of Knet <ul><li>Chemoprints </li></ul><ul><li>aggregate biological data by target </li></ul><ul><li>Biologists can discover off target activity </li></ul><ul><li>HierS Scaffold </li></ul><ul><li>aggregates assay data by scaffolds </li></ul><ul><li>Chemists can quickly discover active features </li></ul><ul><li>of compounds </li></ul>activity targets structural features activity
  14. 14. Chemoprints aggregate the activities of compounds Target Chemoprint Compound Rosiglitazone (Avandia) activity (efficacy +/- SD) targets (cellular and biochemical)
  15. 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. 16. Chemoprints aggregate the activities of compounds Target Chemoprint Compound Rosiglitazone (Avandia) activity (efficacy +/- SD) targets (cellular and biochemical)
  17. 17. Example: Rosiglitazone <ul><li>Rosiglitazone binds to and activates the target, PPAR  </li></ul>PPAR 
  18. 18. Chemoprints aggregate the activities of compounds by target activity (efficacy +/- SD) targets Target Chemoprint Compound Rosiglitazone (Avandia) PPAR  (cellular and biochemical)
  19. 19. Chemoprints aggregate the activities of compounds by target <ul><li>Chemoprint display revealed that PPAR  agonists inhibit EGR1 in certain cellular assays </li></ul>activity (efficacy +/- SD) targets PPAR  (cellular and biochemical) Target Chemoprint Compound Rosiglitazone (Avandia) EGR1 (cellular assays)
  20. 20. Aggregating the activity of compounds by target reveals unexpected activities to biologists <ul><li>literature analysis confirmed that PPAR  agonists inhibit EGR1 pathway </li></ul>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. 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. 22. Protocol Chemoprints display compound activities in individual experimental protocols <ul><li>From this page you can : </li></ul><ul><li>access protocol details </li></ul><ul><li>explore SAR data </li></ul>Target Chemoprint Compound Rosiglitazone (Avandia) view off-target activities Protocol Chemoprint experimental protocols activity (efficacy +/- SD)
  23. 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. 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. 25. Chemoprints allow navigation to SAR table of active scaffolds <ul><li>this path allows the SAR data displayed to consider off-target activities and similar structures </li></ul>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. 26. New features of Knet <ul><li>Chemoprints </li></ul><ul><li>aggregate structural data by assay </li></ul><ul><li>Biologists can discover off target activity </li></ul>targets activity
  27. 27. New features of Knet <ul><li>Chemoprints </li></ul><ul><li>aggregate structural data by assay </li></ul><ul><li>Biologists can discover off target activity </li></ul><ul><li>HierS Scaffold </li></ul><ul><li>aggregates assay data by scaffolds </li></ul><ul><li>Chemists can quickly discover active features </li></ul><ul><li>of compounds </li></ul>structural features activity activity targets
  28. 28. We use HierS scaffold analysis algorithm to classify structural elements in the database 1. identify ring systems ring systems share internal bonds
  29. 29. We use HierS scaffold analysis algorithm to classify structural elements in the database <ul><li>identify ring systems </li></ul><ul><li>trim chains </li></ul>chains are atoms and bonds that are external to rings atoms double bonded to linkers and rings are retained X X
  30. 30. We use HierS scaffold analysis algorithm to classify structural elements in the database <ul><li>identify ring systems </li></ul><ul><li>trim chains </li></ul><ul><li>identify basis scaffolds </li></ul>benzenes are ignored
  31. 31. We use HierS scaffold analysis algorithm to classify structural elements in the database <ul><li>identify ring systems </li></ul><ul><li>trim chains </li></ul><ul><li>identify basis scaffolds </li></ul><ul><li>identify scaffold pairs </li></ul>
  32. 32. We use HierS scaffold analysis algorithm to classify structural elements in the database <ul><li>identify ring systems </li></ul><ul><li>trim chains </li></ul><ul><li>identify basis scaffolds </li></ul><ul><li>identify scaffold pairs </li></ul><ul><li>add ring systems until original scaffold is reached </li></ul>
  33. 33. We use HierS scaffold analysis algorithm to classify structural elements in the database <ul><li>the HierS algorithm for BIRB794 results in 9 scaffolds from the original compound </li></ul>BIRB794
  34. 34. Protocol Chemoprints display data of active structural elements <ul><li>explore how a structural element is active against a particular target </li></ul>Protocol Detail Protocol Chemoprint Target Chemoprint Compound Rosiglitazone (Avandia) view off-target activities view by experiments structural elements (scaffolds) activity increasing CV <ul><li>active scaffolds are selected based on: </li></ul><ul><li>multiple rings </li></ul><ul><li>>50% efficacy </li></ul><ul><li>(all molecules) </li></ul>
  35. 35. We use HierS scaffold analysis algorithm to classify structural elements in the database Scaffold Detail structural elements (scaffolds) Protocol Detail
  36. 36. Scaffolds identified by HierS allow navigation to activity information Structure Detail structural elements (scaffolds) Scaffold Detail
  37. 37. Scaffolds identified by HierS allow navigation to activity information Scaffold Detail Structure Detail view by scaffold structural elements (scaffolds) activity
  38. 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. 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. 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. 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. 42. Where I see the future going <ul><li>R Group Deconvolution could provide insight into why certain compounds containing a scaffold are active while others are not </li></ul><ul><li>Activity Searching would allow chemists and biologists to find compounds that exhibit more complex activity than simple activity against one target </li></ul>

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