New approaches to elucidating Structure Activity Relationships

Chris PetersenTechnical Manager, Informatics

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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

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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

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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

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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">

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Our goal: develop a new way of displaying SAR data

Give biologists all activities for a compound

all

activity

all

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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

structures

all

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New features of Knet

Chemoprints

aggregate biological data by target

Biologists can discover off target activity

activ

ity

targets

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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 compoundsst

ruct

ura

l fea

ture

s

activity

activ

ity

targets

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Chemoprints aggregate the activities of compounds

Target Chemoprint

CompoundRosiglitazone (Avandia)

activ

ity (

effic

acy

+/-

SD

)

targets (cellular and biochemical)

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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

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Chemoprints aggregate the activities of compounds

Target Chemoprint

CompoundRosiglitazone (Avandia)

activ

ity (

effic

acy

+/-

SD

)

targets (cellular and biochemical)

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Example: Rosiglitazone

Rosiglitazone binds to and activates the target, PPAR

PPAR

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Chemoprints aggregate the activities of compounds by target

activ

ity (

effic

acy

+/-

SD

)

targets

Target Chemoprint

CompoundRosiglitazone (Avandia)

PPAR(cellular and biochemical)

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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)

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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)

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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

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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

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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

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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

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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

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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

X

X

chains are atoms and bonds that

are external to rings

atoms double

bonded to linkers and rings are retained

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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

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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

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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

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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

BIRB794

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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)

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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

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Scaffolds identified by HierS allow navigation to activity information

Structure Detailst

ruct

ura

l ele

me

nts

(sca

ffol

ds)

Scaffold Detail

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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

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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

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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

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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

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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