New approaches to elucidating Structure Activity Relationships

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New approaches to elucidating Structure Activity
Relationships

• Chris PetersenTechnical Manager, Informatics

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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
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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

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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 target across 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 target across a variety of assays

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How do users need this information displayed?
SAR table
activity
structures
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But how is the data for the SAR table selected?
SAR table
activity
structures
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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
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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

• Chemists may not know of active structures
  unrelated to compound

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

• Chemists may not know of active structures
  unrelated to compound

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Our goal develop a new way of displaying SAR data

• Give biologists all activities for a compound
• all

all
activity
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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
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New features of Knet

• Chemoprints
• aggregate biological data by target
• Biologists can discover off target activity

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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
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Chemoprints aggregate the activities of compounds
Compound Rosiglitazone (Avandia)
Target Chemoprint
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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
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Chemoprints aggregate the activities of compounds
Compound Rosiglitazone (Avandia)
Target Chemoprint
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Example Rosiglitazone
PPAR?

• Rosiglitazone binds to and activates the target,
  PPAR?

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

• Chemoprint display revealed that PPAR? agonists
  inhibit EGR1 in certain cellular assays

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Aggregating the activity of compounds by target
reveals unexpected activities to biologists
Compound Rosiglitazone (Avandia)
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

• literature analysis confirmed that PPAR? agonists
  inhibit EGR1 pathway

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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
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Protocol Chemoprints display compound activities
in individual experimental protocols
Compound Rosiglitazone (Avandia)
Target Chemoprint
view off-target activities
Protocol Chemoprint

• From this page you can
• access protocol details
• explore SAR data

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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
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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
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Chemoprints allow navigation to SAR tableof
active scaffolds
Compound Rosiglitazone (Avandia)
Target Chemoprint
view off-target activities
view by experiments
Protocol Chemoprint
Protocol Detail
view by structural elements
Standard SAR table

• this path allows the SAR data displayed to
  consider off-target activities and similar
  structures

compounds (with common scaffold)
activity
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New features of Knet

• Chemoprints
• aggregate structural data by assay
• Biologists can discover off target activity

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

1. identify ring systems
2. trim chains

atoms double bonded to linkers and rings are
retained
chains are atoms and bonds that are external to
rings
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We use HierS scaffold analysis algorithm to
classify structural elements in the database
benzenes are ignored

1. identify ring systems
2. trim chains
3. identify basis scaffolds

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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

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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

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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

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

• explore how a structural element is active
  against a particular target

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We use HierS scaffold analysis algorithm to
classify structural elements in the database
Protocol Detail
Scaffold Detail
structural elements (scaffolds)
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Scaffolds identified by HierS allow navigation to
activity information
Scaffold Detail
Structure Detail
structural elements (scaffolds)
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Scaffolds identified by HierS allow navigation to
activity information
Structure Detail
view by scaffold
Scaffold Detail
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Scaffold Target chemoprints show aggregate data
for all compounds that contain scaffold
Structure Detail
view by scaffold
view by activity
Scaffold Detail
Scaffold Chemoprint
aggregate activity data for 34 compounds
containing this scaffold
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Scaffold Target chemoprints can highlight
activity intrinsic to a scaffold
Structure Detail
view by scaffold
view by activity
Scaffold Detail
Scaffold Chemoprint
aggregate activity data for 34 compounds
containing this scaffold
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Scaffold Target chemoprints can highlight
activity intrinsic to a scaffold
Structure Detail
view by scaffold
view by activity
Scaffold Detail
Scaffold Chemoprint
Activity not tightly tied to scaffold
aggregate activity data for 34 compounds
containing this scaffold
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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
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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