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This is a presentation I gave at the San Diego Bioinformatics Forum on October of 2006.
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New approaches to elucidating Structure Activity Relationships
Chris PetersenTechnical Manager, Informatics
22
Who am I?
Programmer
previously:Distance LearningPerformance ManagementCustomer Relationship ManagementStreaming Video
currently:KalypsysSystem Architect of Knet, a custom scientific data management system
33
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
44
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
55
How do users need this information displayed?
structures
act
ivity
SAR table
66
But how is the data for the SAR table selected?
structures
act
ivity
SAR table
77
structures
acti
vity
SAR table
But how is the data for the SAR table selected?
Biologists may not know all of the
targets the compound is
affecting
88
structures
act
ivity
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
99
structures
act
ivity
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
<speculation X=“incomplete" Y=“incomplete">
1010
Our goal: develop a new way of displaying SAR data
Give biologists all activities for a compound
all
activity
all
1111
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
1212
New features of Knet
Chemoprints
aggregate biological data by target
Biologists can discover off target activity
activ
ity
targets
1313
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 compoundsst
ruct
ura
l fea
ture
s
activity
activ
ity
targets
1414
Chemoprints aggregate the activities of compounds
Target Chemoprint
CompoundRosiglitazone (Avandia)
activ
ity (
effic
acy
+/-
SD
)
targets (cellular and biochemical)
1515
Our database structure enables useful aggregation
Target
Experiment
Protocol
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
1616
Chemoprints aggregate the activities of compounds
Target Chemoprint
CompoundRosiglitazone (Avandia)
activ
ity (
effic
acy
+/-
SD
)
targets (cellular and biochemical)
1717
Example: Rosiglitazone
Rosiglitazone binds to and activates the target, PPAR
PPAR
1818
Chemoprints aggregate the activities of compounds by target
activ
ity (
effic
acy
+/-
SD
)
targets
Target Chemoprint
CompoundRosiglitazone (Avandia)
PPAR(cellular and biochemical)
1919
activ
ity (
effic
acy
+/-
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)
CompoundRosiglitazone (Avandia)
2020
Chemoprint display revealed that PPAR agonists inhibit EGR1 in certain cellular assays
activ
ity (
effic
acy
+/-
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 30 2002
CompoundRosiglitazone (Avandia)
2121
Target Chemoprints allow biologists to access compound activities in individual experiments
activ
ity (
effic
acy
+/-
SD
)
targets
EGR1(cellular assays)
PPAR(cellular and biochemical)
Target Chemoprint
CompoundRosiglitazone (Avandia)
2222
Protocol Chemoprints display compound activities in individual experimental protocols
Target Chemoprint
CompoundRosiglitazone (Avandia)
view off-target activities
Protocol Chemoprint
experimental protocols
activ
ity (
effic
acy
+/-
SD
)
From this page you can: • access protocol details• explore SAR data
2323
Protocol Chemoprints allow users to access data of active structural elements
Protocol Chemoprint
activ
ity (
effic
acy
+/-
SD
)
experimental protocols
Target Chemoprint
CompoundRosiglitazone (Avandia)
view off-target activities
2424
Protocol Chemoprints display data of active structural elements
Protocol Detail
stru
ctur
al e
lem
ent
s (s
caff
old
s)
Protocol Chemoprint
Target Chemoprint
CompoundRosiglitazone (Avandia)
view off-target activities
view by experiments
activity
2525
Chemoprints allow navigation to SAR tableof active scaffolds
this path allows the SAR data displayed to consider off-target activities and similar structures
Protocol Detail
Protocol Chemoprint
Target Chemoprint
CompoundRosiglitazone (Avandia)
Standard SAR table
view off-target activities
view by experiments
view by structural elements
com
poun
ds
(with
com
mon
sca
ffol
d)
activity
2626
targets
New features of Knet
Chemoprints
aggregate structural data by assay
Biologists can discover off target activity
activ
ity
2727
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 compoundsst
ruct
ura
l fea
ture
s
activity
activ
ity
targets
2828
We use HierS scaffold analysis algorithm to classify structural elements in the database
1. identify ring systems
ring systems share
internal bonds
2929
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
3030
We use HierS scaffold analysis algorithm to classify structural elements in the database
1. identify ring systems 2. trim chains3. identify basis scaffolds
benzenes are ignored
3131
We use HierS scaffold analysis algorithm to classify structural elements in the database
1. identify ring systems 2. trim chains3. identify basis scaffolds4. identify scaffold pairs
3232
We use HierS scaffold analysis algorithm to classify structural elements in the database
1. identify ring systems 2. trim chains3. identify basis scaffolds4. identify scaffold pairs5. add ring systems until original
scaffold is reached
3333
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
3434
Protocol Chemoprints display data of active structural elements
Protocol Detail
Protocol Chemoprint
Target Chemoprint
CompoundRosiglitazone (Avandia)
view off-target activities
view by experimentsst
ruct
ura
l ele
me
nts
(sca
ffol
ds)
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)
3535
We use HierS scaffold analysis algorithm to classify structural elements in the database
Scaffold Detailst
ruct
ura
l ele
me
nts
(sca
ffol
ds)
Protocol Detail
3636
Scaffolds identified by HierS allow navigation to activity information
Structure Detailst
ruct
ura
l ele
me
nts
(sca
ffol
ds)
Scaffold Detail
3737
Scaffolds identified by HierS allow navigation to activity information
Scaffold Detail
Structure Detail view by scaffold
stru
ctur
al e
lem
ent
s (s
caff
old
s)
activity
3838
Scaffold Target chemoprints show aggregate data for all compounds that contain scaffold
view by activityScaffold Detail
Structure Detail view by scaffold
Scaffold Chemoprint
aggregate activity data for 34 compounds
containing this scaffold
3939
Scaffold Target chemoprints can highlight activity intrinsic to a scaffold
view by activityScaffold Detail
Structure Detail view by scaffold
Scaffold Chemoprint
Activity not tightly tiedto scaffold
aggregate activity data for 34 compounds
containing this scaffold
4040
Scaffold Target chemoprints can highlight activity intrinsic to a scaffold
view by activityScaffold Detail
Structure Detail view by scaffold
Scaffold Chemoprint
Activity not tightly tiedto scaffold
Activity very tightly tiedto scaffold
aggregate activity data for 34 compounds
containing this scaffold
4141
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
4242
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