Transcript New approaches to elucidating SAR relationships

New approaches to elucidating
Structure Activity Relationships
Chris Petersen
Technical Manager, Informatics
Who am I?
previously:
Distance Learning
Performance Management
Customer Relationship Management
Streaming Video
Programmer
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
need to
to know
know what
what compounds
compounds are
are active
active against
against aa
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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How do users need this information displayed?
activity
SAR table
structures
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But how is the data for the SAR table selected?
activity
SAR table
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
activity
SAR table
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
activity
SAR table
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?
<speculation X=“incomplete" Y=“incomplete">
Biologists may
not know all of the
targets the
compound is
affecting
activity
SAR table
structures
Chemists may not know of active
structures unrelated to compound
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Give biologists all activities for a compound
all
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activity
Our goal: develop a new way of displaying SAR data
Give biologists all activities for a compound
activity
Our goal: develop a new way of displaying SAR data
Give chemists all compounds with active structural elements
structures
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activity
New features of Knet
targets
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Chemoprints
aggregate biological data by target
Biologists can discover off target activity
activity
New features of Knet
structural features
targets
activity
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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
Chemoprints aggregate the activities of compounds
Compound
Rosiglitazone (Avandia)
activity
(efficacy +/- SD)
Target Chemoprint
targets (cellular and biochemical)
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Our database structure enables useful aggregation
Target
Experiments are instances of a protocol and all
protocols have a defined target
Protocol
Experiment
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)
activity
(efficacy +/- SD)
Target Chemoprint
targets (cellular and biochemical)
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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)
activity
(efficacy +/- SD)
Target Chemoprint
PPAR
(cellular and biochemical)
targets
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Chemoprints aggregate the activities of compounds by target
Compound
Rosiglitazone (Avandia)
activity
(efficacy +/- SD)
Target Chemoprint
EGR1
(cellular assays)
PPAR
(cellular and biochemical)
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
FuDagger et al.
J. Biol. Chem., Vol.
277, Issue 30 2002
activity
(efficacy +/- SD)
Kim et al.
Toxicological
Sciences, 2005
EGR1
(cellular assays)
PPAR
(cellular and biochemical)
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)
activity
(efficacy +/- SD)
Target Chemoprint
EGR1
(cellular assays)
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PPAR
(cellular and biochemical)
targets
Protocol Chemoprints display compound activities in
individual experimental protocols
Compound
Rosiglitazone (Avandia)
Target Chemoprint
activity
(efficacy +/- SD)
Protocol Chemoprint
experimental protocols
From this page you can:
• access protocol details
• explore SAR data
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view off-target activities
Protocol Chemoprints allow users to access data of
active structural elements
Compound
Rosiglitazone (Avandia)
Target Chemoprint
activity
(efficacy +/- SD)
Protocol Chemoprint
experimental protocols
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view off-target activities
Protocol Chemoprints display data of
active structural elements
Compound
Rosiglitazone (Avandia)
Target Chemoprint
Protocol Chemoprint
structural elements
(scaffolds)
Protocol Detail
activity
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view off-target activities
view by experiments
Chemoprints allow navigation to SAR table
of active scaffolds
Compound
Rosiglitazone (Avandia)
Target Chemoprint
Protocol Chemoprint
Protocol Detail
view off-target activities
view by experiments
view by structural elements
compounds
(with common scaffold)
Standard SAR table
this path allows the
SAR data displayed to
consider off-target
activities and similar
structures
activity
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activity
New features of Knet
targets
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Chemoprints
aggregate structural data by assay
Biologists can discover off target activity
activity
New features of Knet
structural features
targets
activity
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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
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
X
1.
2.
X
atoms
double
bonded to
linkers and
rings are
retained
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chains are
atoms and
bonds that
are external
to rings
identify ring systems
trim chains
We use HierS scaffold analysis algorithm to classify
structural elements in the database
benzenes
are ignored
1.
2.
3.
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identify ring systems
trim chains
identify basis scaffolds
We use HierS scaffold analysis algorithm to classify
structural elements in the database
1.
2.
3.
4.
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identify ring systems
trim chains
identify basis scaffolds
identify scaffold pairs
We use HierS scaffold analysis algorithm to classify
structural elements in the database
1.
2.
3.
4.
5.
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identify ring systems
trim chains
identify basis scaffolds
identify scaffold pairs
add ring systems until original
scaffold is reached
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
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Protocol Chemoprints display data of
active structural elements
Compound
Rosiglitazone (Avandia)
Target Chemoprint
Protocol Chemoprint
view off-target activities
view by experiments
active scaffolds are
selected based on:
• multiple rings
•>50% efficacy
(all molecules)
structural elements
(scaffolds)
Protocol Detail
increasing CV
activity
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
structural elements
(scaffolds)
Scaffold Detail
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Scaffolds identified by HierS allow navigation to
activity information
Scaffold Detail
structural elements
(scaffolds)
Structure Detail
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Scaffolds identified by HierS allow navigation to
activity information
Structure Detail
structural elements
(scaffolds)
Scaffold Detail
activity
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view by scaffold
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
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Scaffold Target chemoprints can highlight activity intrinsic to a 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
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Scaffold Target chemoprints can highlight activity intrinsic to a scaffold
Structure Detail
view by scaffold
Scaffold Detail
view by activity
Scaffold Chemoprint
Activity not tightly tied
to scaffold
Activity very 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
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