New approaches to elucidating Structure Activity Relationships Chris Petersen Technical Manager, Informatics

2 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 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 4 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 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

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

8 8 structures activity SAR table 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

9 9 structures activity SAR table 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

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 structural features activity targets

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

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

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

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 targets New features of Knet Chemoprints aggregate structural data by assay Biologists can discover off target activity 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 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 1.identify ring systems 2.trim chains X X chains are atoms and bonds that are external to rings atoms double bonded to linkers and rings are retained

30 We use HierS scaffold analysis algorithm to classify structural elements in the database 1.identify ring systems 2.trim chains 3.identify basis scaffolds benzenes are ignored

31 We use HierS scaffold analysis algorithm to classify structural elements in the database 1.identify ring systems 2.trim chains 3.identify basis scaffolds 4.identify scaffold pairs

32 We use HierS scaffold analysis algorithm to classify structural elements in the database 1.identify ring systems 2.trim chains 3.identify basis scaffolds 4.identify scaffold pairs 5.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 Protocol Detail Protocol Chemoprint Target Chemoprint Compound Rosiglitazone (Avandia) view off-target activities view by experiments structural elements (scaffolds) activity explore how a structural element is active against a particular target 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 Activity not tightly tied to scaffold aggregate activity data for 34 compounds containing this 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 Activity very tightly tied to scaffold aggregate activity data for 34 compounds containing this 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