Make the right decisions with data you can trust

2AurPASS

Instructions for attendees

Due to the High number of attendees:

Before starting Use your full name for Identification

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During the webinarUse the chat for questions

At the End You can ask your questions orally

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07/04/2011

Predicting Pharmacology & Safety Profiles Using AurPASS

4AurPASS

Aureus Sciences

Knowledge-Based Pharmacological Profiling

AurPROFILER: visualizing the Known

Filling the Gap using AurPASS to Predict the Unknown

AurPASS

PASS Predictive Algorithm

Added Value of AurSCOPE Knowledgebases

AurPASS Ion Channels & AurPASS Kinase

Live Demo: Applications for Safety Pharmacology Assessment

Discussion

Agenda

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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.

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Aureus Approach

7AurPASS

AurSCOPE Knowledge Databases Target Pharmacological Space

2002 2004 2005 2008 2009

Aureus Terminology, Glossary, Thesaurii>70 glossaries and dictionaries, 5-10 taxonomies, >65,000 terms and synonyms, IUPHAR,

SwissPROT

GPCR

BiologicalProtocols

Unique Ligands

BiologicalActivities

PublicationsAnalyzed

KinaseIon ChannelNuclear Receptor

Protease

146,426354,323

670,407 1,243,793

10,206 including 6,806 patents

13,303 including 6,966 patents

32,588 including 15,281 patents

4,668 including2,484 patents

98,439

275,044

4,226 including1,060 patents

36%

23%16%

13%8% 2% 1%

Activities by Protocol Types

BindingIn vivoElectrophys.FluxIsol. OrganCell 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

BindingSecond messengerIn vivoIsolated organCell behaviourFluxEnzymology

418,202

124,313

66%20%

7%5% 2%

Activities by Protocol Types

Enzymology

Cell proliferation

In Vivo

Binding

Flux

186,047

32%

37%

11%

9%6%

2%2%

Activities by Protocoles types

BindingTransactivationIn VivoCell proliferationInductionFluxProtein interaction

48,500

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8AurPASS

AurSCOPE Knowledge Databases ADME/DDI & TOX

BiologicalProtocols

Unique Ligands

BiologicalActivities

PublicationsAnalyzed

hERGADME/DDI Hepatotox

Aureus Terminology, Glossary, Thesaurii>100 glossaries and dictionaries, 5-10 taxonomies, >65,000 terms and synonyms,

IUPHAR, SwissPROT

13,88734,872 compounds including 4,050 metabolites

33,210462,785

2,291 including 547 Patents

12,165 including200 FDA Reviews

3,600 Articles (67 patents, 75 FDA Studies)

70,035

845 Drugs

1% 1%3%

4%28%

61%

Activities by Protocol Types

BiochemistryCell behaviourBindingInductionFluxEnzymologyIn VivoOthers

67%

14%

13%

4% 1% 1%

Actvities by Protocol Types

PK / DDIMetabolism (Enzyme)Inhibtion (Enzyme)TransportInductionBinding

53%

27%

10%10%

Activities by Protocol Types

ElectrophysiologyIn VivoBindingFlux

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Make The Right Decision With Data You Can Trust

AurQUESTData mining

AurPROFILERData analysis & NavigationMedicinal Chemistry Space

AurPASSPredict Biological Activities SpectraDDI Predict

AurPASS

10AurPASS

AurPROFILER – Pharmacology Profiles of 74 Drugs (Big Pharma)

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11AurPASS

Filling the Gap Using AurPASS in silico Predictions

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Aureus

Prediction of

Activity

Spectra for

Substances

12AurPASS

Predicting New Activities on Selected big Pharma Drugs

277 Ion Channels

86

Sel

ect

ed

Mol

ecu

les

fro

m M

ER

CK

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13AurPASS

Over Forty Publications with Independent Confirmation of PASS Predictions…

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14AurPASS

Training SetSAR data extracted from individual AurSCOPE databases

Chemical & biological post-processing

Chemical StructuresMultilevel Neighborhoods of Atoms (MNA) descriptors

SAR BaseDiverse chemical structures and associated MNA descriptors

Associated qualitative biological activity types

Prediction AlgorithmPASS Bayesian approach

Models ValidationLOO and L20%O validations

External dataset

AurPASS

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15AurPASS

Training SetSAR data extracted from individual AurSCOPE knowledgebases

Chemical & biological post-processing

Chemical StructuresMultilevel Neighborhoods of Atoms (MNA) descriptors

SAR BaseDiverse chemical structures and associated MNA descriptors

Associated qualitative biological activity types

Prediction AlgorithmPASS Bayesian approach

Models ValidationLOO and L20%O validations

External dataset

AurPASS

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16AurPASS

Added Value of Structured Data for Predictive Models

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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

17AurPASS 07/04/2011

Assigning Activity Classes

AurPASS Activity Types

18AurPASS

Multilevel Neighbourhoods of Atoms (MNA) descriptors are generated on the basis of the connection table of 2D molecular structures (including hydrogens)

Bond types are not specified

MNA are generated as recursively defined • Zero level MNA descriptor for each atom is the atom type itself;

• The first level MNA descriptor include the atom’s zero level descriptors and zero-level descriptors of its neighboring atoms sorted lexicographically …

Encoding Chemical Structures: MNA Descriptors

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MNA descriptors dictionary

19AurPASS

Encoding Chemical Structures: MNA Descriptors

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MNA/0: C

MNA/1: C(CN-H)

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

CC

H

C

O

O

NC

H

C

CH

H H

CC

H

C

O

O

NC

H

C

CH

H H

CC

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))

20AurPASS

PASS Approach for Biological Activity Prediction

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According to the Bayes' theorem, the probability P(A|S) that the compound S has activity (or inactivity) A, equals to:

P(A|S) = P(S|A)•P(A)/P(S)

If the descriptors of organic compound D1, ..., Dm are independent, then:

P(S|A) = P(D1, ..., Dm|A) = ПiP(Di|A)

P(A) and P(A|Di) are calculated as sums through all compounds of the training set:

k ik

k kiki )(Dg

(A))w(Dg)|DP(A

i k ik

i k kik

)(Dg

(A))w(DgP(A)

Filimonov D.A., Poroikov V.V. (2008). Probabilistic Approach in Virtual Screening. In: Chemoinformatics Approaches to Virtual Screening. Alexander Varnek and Alexander Tropsha, Eds. RSC Publishing.

21AurPASS

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

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22AurPASS

AurPASS Ion Channels – Version 1.2.1

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Training Set47 938 molecules517 Activity Types

Mean Accuracy of Prediction: 98%

Test Set2244 molecules113 Activity types

Mean Accuracy of Prediction: 90%

Prediction Accuracy using AurPASS

0

20

40

60

80

1005HT-3

AMPA

AMPA/Kainate

ASIC

Ca2+

CFTR

ENaC

GABAA

InsP3

K+KainateKATP

L-type Ca2+

Na+

nACh

NMDA

N-type Ca2+

P2X

TRPA

TRPV

T-type Ca2+AurPASS Activity

IAP

24AurPASS

How AurPASS Works?

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Ion ChannelsKinasesGPCRsProteasesNuclear ReceptorsOff-Targets

25AurPASS

AurPASS Ion Channels

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Live Demo

26AurPASS

AurPASS Product Line

07/04/2011

May, 2011AurPASS Off-TargetsAurPASS GPCRAurPASS Nuclear Receptors

Application Note and Evaluation Software

available Under Request

27AurPASS

Thank you for your

attention

Aureus Sciences 174, Quai de Jemmapes 75010 Paris, FRANCE

www.aureus-pharma.com

07/04/2011