Make the right decisions with data you can trust

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2AurPASS

Prediction of Adverse Drug

Reactions Mediated by

Off-Targets Using AurPASS

Safety and Adverse Effects

01/07/2011 4

Every year about 2 million patients in the United States are affected

by a serious adverse drug reaction.

This results in approximately 100,000 fatalities, making ADRs the

fourth leading cause of death in the U.S.

The consequence is a huge burden on national economies, which is

estimated to be $136 billion annually in the U.S.

Over the past 10 years, 19 broadly used marketed drugs were

withdrawn after presenting unexpected severe side effects, with

Rofecoxib and Cerivastatin.

AurPASS

What is an off-target or anti-target?

Off-Targets and Preclinical Safety Pharmacology

Case Studies of Drug Failures Related to Off-Target Activities

Off-Targets in Gene Families

Ion Channels

GPCRs

Nuclear Receptors

Cytochrome P450

Transporters

Delimiting the Chemical Space of Off-Targets

Predicting Off-Targets

Off-Targets in Gene Families

5AurPASS

Aureus at a Glance

Aureus is a knowledge and information management solutions provider

for the Life Science industry located in Paris.

Over the past 10 years the company has developed a unique

knowledge production platform which stores, indexes and organizes

critical chemical and bioactivity information including experimental in

vitro and in vivo protocols from the public or private literature.

Aureus employees 20 high level scientists (PhD and MSc) including

scientific and IT project leaders and documentation analysts

Aureus is funded by institutional investors like CDC Entreprise, AXA

Provate Equity, OTC Asset Management and is part of the OSEO

Excellence innovation team.

07/04/2011 6AurPASS

Aureus 10 Years Experience of Building SAR Databases

7/1/2011 7AurPASS

AurSCOPE Knowledge Databases Target Pharmacological Space

2002 2004 2005 2008 2009

GPCR

Biological

Protocols

Unique

Ligands

Biological

Activities

Publications

KinaseIon ChannelNuclear

ReceptorProtease

146,426354,323

670,4071,243,793

10,206 including

6,806 patents

13,303 including

6,966 patents

32,588 including

15,281 patents

4,668 including

2,484 patents

98,439

275,044

4,226 including

1,060 patents

36%

23%

16%

14%

8% 2%1%

Activities by Protocol Types

Binding

In vivo

Electrophys.

Flux

Isol. Organ

Cell Behav.

Others

1% 2%7%

13%

77%

Activities by Protocol Types

FluxBindingIn VivoCell behaviourEnzymology

54%

17%

15%

7%3%

3% 1%

Activities by Protocol Types

Binding

Second messenger

In vivo

Isolated organ

Cell behaviour

Flux

Enzymology

418,202

124,313

66%

20%

7%5% 2%

Activities by Protocol Types

Enzymology

Cell proliferation

In Vivo

Binding

Flux

186,047

32%

37%

12%

9%6%

2%2%

Activities by Protocoles types

Binding

Transactivation

In Vivo

Cell proliferation

Induction

Flux

Protein interaction

48,500

8AurPASS

AurSCOPE Knowledge Databases ADME/DDI & TOX

Biological

Protocols

Unique

Ligands

Biological

Activities

Publications

ADME/DDI

34,872 compounds

including 4,050 metabolites

462,785

12,165 including

200 FDA Reviews

67%

14%

13%

4% 1%1%

Activities by Protocol Types

PK / DDI

Metabolism (Enzyme)

Inhibtion (Enzyme)

Transport

Induction

Binding

9AurPASS

Off-Targets

107,646 compounds

315,200

10,700

AurSCOPE GPS : Global Pharmacological Database

01/07/2011 10

GPCR Ion

Channel

Kinase NHR Protease

2009

ADME Off

Targets

2010 2011

AurPASS

Make The Right Decision With Data You Can Trust

AurQUESTData mining

AurPROFILERData analysis & Navigation

Medicinal Chemistry Space

AurPASSPredict Biological

Activities SpectraDDI Predict

AurPASS 11

Filling the Gap Using AurPASS in silico Predictions

12

Aureus

Prediction of

Activity

Spectra for

Substances

AurPASS

GPCR Ion

Channel

Kinase NHR Protease ADME Off

Targets

Predicting New Activities on Selected big Pharma Drugs

Off-Targets

Se

lecte

dM

ole

cu

les

fro

mP

ha

rma

Pip

elin

e

13AurPASS

Over Forty Publications with Independent Confirmation of

PASS Predictions…

14AurPASS More References in aureus-sciences.com/ResourceCenter

Training Set

SAR data extracted from individual AurSCOPE databases

Chemical & biological post-processing

Chemical Structures

Multilevel Neighborhoods of Atoms (MNA) descriptors

SAR Base

Diverse chemical structures and associated MNA descriptors

Associated qualitative biological activity types

Prediction Algorithm

PASS Bayesian approach

Models Validation

LOO and L20%O validations

External dataset

AurPASS

15AurPASS

AurPASS Off-Target Modules

16AurPASS

Training Set

SAR data extracted from individual AurSCOPE knowledgebases

Chemical & biological post-processing

Chemical Structures

Multilevel Neighborhoods of Atoms (MNA) descriptors

SAR Base

Diverse chemical structures and associated MNA descriptors

Associated qualitative biological activity types

Prediction Algorithm

PASS Bayesian approach

Models Validation

LOO and L20%O validations

External dataset

AurPASS

17AurPASS

Selected Off-Targets and Associated ADRs

7/1/2011 18

Target family Target Adverse Drug Reaction

GPCR • 5HT-2A

• 5HT-2B

• 5HT-2C

• Alpha1A-adrenergic

• Beta1-adrenergic

• H1

• H2

• M1

• M2

• D2

• Opioid (, , )

• Vasoconstriction, Ischemia, Hypertension, Anxiety

• Valvular heart disease

• Weight gain, Obesity

• Orthostatic hypotension, Dizziness and fainting spells

• Dysrhythmias, Bronchoconstriction, Cardiac failure

• Extrapyrimidal syndrome, Sedation, Hypotension, Dizziness

• Diarrhoea, Muscle pains, Transient rashes, Hypergastrinaemia

• Attention deficits, Hallucination

• Bradycardia, Decreased/increased heart rate and contractility

• Extrapyramidal syndrome, Tardive dyskinesia

• Depression, Sedation, Dependence, Reverse analgesia

Ion channels • hERG Kv11.1

• NMDA

• Na channel

• QT prolongation (Torsades de Pointes)

• Psychomotor retardation, Dysmorphic features, Cataracts

• Ataxia, vertigo, Megaloblastic anaemia, Foetal malformation

Nuclear Receptors • PXR

• LXR

• FXR

• PPAR

• Fertility changes, teratogenic effects, Drug-drug interactions, Dyslipidemias

• Fertility changes, teratogenic effects, Drug-drug interactions, Dyslipidemias

• Fertility changes, teratogenic effects, Drug-drug interactions, Dyslipidemias

• Carcinogenicity, Myopathy and rhabdomyolysis, weight gain

Cytochromes P450 • CYP1A2

• CYP3A4

• CYP2D6

• CYP2C9

• CYP2C19

• Sedation, confusion, and respiratory depression, Tardive dyskinesia

• Myositis, myopathy, renal failure, respiratory failure

• Arrhythmias, Bradycardia, Confusion, Lactic acidosis, Hepatotoxicity

• Haemorrhage, Hypoglycaemia, Phenytoin toxicity

• Neurotoxicity, Prolonged sedation

AurPASS

SAR information for these targets can be displayed in our portal aureus-sciences.com

Content Description of Aureus Knowledgebases….

7/1/2011 19AurPASS

Added Value of Aureus Data for Predictive Models

20

Chemical Processing

Biological Processing

• No Peptides

• No mixtures

• Inorganic and metalo-organic removal

• Charge standardization

• Biological protocols

• Target hierarchy

• Target species, cell lines and tissues

• Biological activity parameters

• Ligand action on target

hERG Channel

AurPASS

217/1/2011

Added Value of Aureus Data for Predictive Models

Assigning Activity Classes

Molecules &

SAR Data

Actives &

Inactives

AurPASS Activity Types

PASS

Training/Test

Sets

Actives &

Inactives

AurPASS

Encoding Chemical Structures: MNA Descriptors

22

MNA/0: CCC

H

C

O

O

NC

H

C

CH

H H

MNA/2

C(C(CC-H)C(CC-C)-H(C))C(C(CC-H)C(CN-H)-H(C))C(C(CC-H)C(CN-H)-C(C-O-O))C(C(CC-H)N(CC)-H(C))C(C(CC-C)N(CC)-H(C))N(C(CN-H)C(CN-H))-H(C(CC-H))-H(C(CN-H))-H(-O(-H-C))-C(C(CC-C)-O(-H-C)-O(-C))-O(-H(-O)-C(C-O-O))-O(-C(C-O-O))

AurPASS

CC

H

C

O

O

NC

H

C

CH

H H MNA/1: C(CN-H)

CC

H

C

O

O

NC

H

C

CH

H H MNA/2: C(C(CC-H)N(CC)-H(C))

Predicted values are “Probability Estimations”

In all AurPASS modules, “Actives” are defined by a biological

threshold less than 10 µM.

The list of activities which are probable for a particular compound

with the estimates for each activity of :

Pa: probability to be active

Pi: probability to be inactive

Pa and Pi are calculated independently: Pa + Pi 1

Pa (Pi) can be considered as the probability of the compound

belonging to classes of active (inactive) compounds

PASS Approach for Biological Activity Prediction

23AurPASS

Internal Validation of AurPASS Off-Target Models

AurPASS

AurSCOPE Databases are Quarterly Updated (4 releases/Year)

Improvement of dataset over time in terms of diversity

Updating/Testing generated models with new data

External Validation of AurPASS Off-Targets Models

25AurPASS

Training SetRelease n-1

Test SetRelease n

3 months later

AurPASS

Ion

Channels

47 938 Molecules

517 Activity Types

Mean Accuracy of Prediction: 98%

2 244 new Molecules

113 Activity Types

Mean Accuracy of Prediction: 90%

7/1/2011 26

Can be downloaded from aureus-sciences.com/ResourceCenter

AurPASS Off-Target

…is a desktop application licensed on a user basis.

It contains the Aureus Off-Target dataset model.

Off-Target Database

…is the complete database accessible through the Aureus Web Portal and licensed on

an annual subscription mode

AurPASS Product Line Aureus On Line Databases

AurPASS Ion Channel Ion Channel 365 Targets / 130 000 Molecules

AurPASS Kinase Kinase 1010 Targets / 190 000 Molecules

AurpASS GPCR GPCR 555 Targets / 380 000 Molecules

AurPASS Off Target Off Target 70 Targets / 107 000 Molecules

27

AurPASS Offers

AurPASS

Aureus Scienceswww.aureus-sciences.com

contact@aureus-sciences.com

Tel: +33 1 40 18 57 57

Or Aureus Distributors

AKOS (Germany) www.akosgmbh.de

Ariadne Genomics (U.S.) www.ariadnegenomics.com

Patcore (Japan) www.patcore.com

Pharmogo (China) www.pharmogo.com

28

For More Information

AurPASS

Thank you for

your attention

174, Quai de Jemmapes

75010 Paris, FRANCE

www.aureus-sciences.com

29