In silico predictive toxicology new disruptive technology

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In silico

predictive toxicology

new disruptive technology

Romain GUIDON

Business Development

+33 625 14 17 66

romain.guidon@bioquanta.net

Enabling Predictive and Personalized Medicine

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>

Company Profile

Enabling Predictive and Personalized Medicine

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BioQuanta Team

A multidisciplinary team : 26 employees + Consultants

An independent group : 80% held by founders (3 scientists + 1 entrepreneur)

Dr. Marc Conti

PhD, Pharm D

Hospital practitioner at AP-HP,

Biology, Biochemistry

Pr. Sylvain Loric

PhD Pasteur, Pharm D,

Head of Biology Dept. at AP-HP,

specialized in genetics

Pr. Philippe Manivet

PhD Polytechnique, Pharm D

Hospital practitioner at AP-HP

Biology, Bioinformatics

Jean-Michel Mauclaire

ESCP Europe, CPA

CEO

Thierry Gérardi

MBA IAE Sorbonne

Marketing, Comm., HR

Remi Rabeuf

MBA

Managing Director

Pr. Flavio Toma

PhD Univ. Evry, structural biology

CSO

Thierry Delvienne

Pharm D

Admin., Sr. Mgmt. ,

Business Dev. Europe LGC

François Hamon

Pharm D

Finance advisor

for biotech and pharma.

MANAGEMENT

SCIENTIFIC ADVISORY BOARD

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BioQuanta group

BioQuanta SA is listed on NYSE-EURONEXT Paris, Marché libre

BioQuanta Corp.

BioQuanta SA

TheraQuanta

Bioinsignis

Compagnie Holding

Science as a service

Kits de Diagnostic

Tracking and

anticounterfeiting

solution

Therapeutical molecules

design & repositioning

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Our business model : 3 complementary pillars

ADME-Tox

Prediction of molecule

efficacy and toxicity

Metabolic exploration

Effects of exogen compound

on cells or organism

DIAGNOSTIC KITS

ADNc1

ADNc3

MDA

ANGIM

NMI

Standardisation PCR/Arrays

COMPANION DIAGNOSTIC

Ability to design and develop

on demand companion Dx

tests

Traçabiliy / Anti-counterfeiting

solution

Services

Therapeutics

Diagnostic

Pipeline 8 programs

Scientific expertise

Technological platfoms

1 patented kit : ADNc1

2 patents under submission

ADME-Tox

Effects of a molecule on

living organism

ADME-Tox

Effects of a molecule on a

programmed stem cell

UNDER DEVELOPMENT

Cancer angiogenesis

Antidepressant

Alzheimer

primary tumor

cancer

Infertility

Anti-infectious/ HIV

Malaria

Chemokines

R

BioQuanta SA

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Novel integrated approach

Enabling Predictive and Personalized Medicine

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Enabling predictive and personalized medicine to take place

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1 Predictive

Toxicity

2 Predictive

ADME

3 Patient

Categorization

4 Drug

prescription &

Monitoring

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A service platform designed by

Toxicity prediction and characterization

in silico

disruptive technology

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Scalable modules for selecting the best compounds

1000 100 10 1 Nb. compounds

Prediction and ranking

Characterization

Toxicity check

Rapid screening

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Enpoints list

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Carcinogenicity

Mutagenicity

_{organs toxicity}

Reproductive

PBT, vP, vB

Endocrine

_disruptor

Cytotoxicity

Genotoxicity

Teratogenicity

_{(hERG blockers)}

Cardiotoxicity

Hepatotoxicity

Renal toxicity

Gastrointestinal

_toxicity

Lungs toxicity

Neurotoxicity

Irritancy

Ocular Toxicity

_{Sensitization}

Respiratory

_{Sensitization}

Skin

Ecotox: Algae

Ecotox: Bird

Ecotox: Daphne

Ecotox: Fish

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3 unique technology components

MultiDIP® provides accurate and reliable toxicity predictions and

characterizations based on :

1. A

pharmacophore

that represents

isomeric and conformational variants

of

molecules

2. An extensive pharmacophore

database

of toxic compounds

(

>1.7 million pharmacophores

)

3. An extensive bibliographic system for an

expert understanding

of the

biological context

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Pharmacophore generation

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2D/3D

3D+Pharmacophore

Pharmacophore

Interaction

pharmacophore-protéine

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Molecular predictions from molecular models

MultiDIP® Toxicity Screening

• Based on a multidimensional representation of the

entire molecule

• No pre-grouping required

pharmacophores are directly compared for overlap in multiple dimensions

• No “training set”

• All relevant

conformers

and

isomers

can be screened

• Accurately represents geometric and

electronic structure

features

important for binding

Existing QSARs

• Mainly based on 2D

fragments

of an entire molecule

• Fragments are analyzed for

statistical correlations

with toxicity

• Require laborious pre-categorization of molecules to find the right QSAR

• Highly dependent on the training set

• Does not represent molecular flexibility (conformational contribution to binding)

• Does not capture whole-molecule electronic structure

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Shortcomings of 2D similarity

2D Versus 3D

: Enantiomers Differentiation

S t a n d a r d A p p r o a c h

B i o Q u a n t a ’ s A p p r o a c h

Example:

Thalidomide

(anxiolotic)

Teratogenic Enantiomers

(S)-Thalidomide (S) Enantiomer (R)-Thalidomide (R) Enantiomer

2D Structure

It’s not possible to differentiate

enantiomers

’ properties of

molecules

Thalidomide

Classical 2D Structure Mirror

3D Pharmacophores

Enantiomers

’ properties differentiation is possible

(R)-Thalidomide Pharmacophore

(S)-Thalidomide Pharmacophore

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Application

Reference compounds, targets

Multidimensional models

TOXICITY

DSS TOX 15.000 compounds

1,7 Million

10.000 natural / non-toxic

1 million+ natural/non toxic

ADME

120 relevant targets

1 million+

SAFETY PHARMACOLOGY

50 relevant targets

0,5 million+

PROFILING

2930 GPCR

500 ion channels and other targets

7,5 million+

Databases

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DATA WHAREHOUSE : OLAP cube for fast analysis of data

• Allows manipulating and analyzing data from multiple perspectives

• Overcomes a limitation of relational databases

• Near instantaneous analysis and display of large amounts of data

Extract, transform, and load data

into the repository, and manage

and retrieve metadata

ZonoCube

®

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Virtual screening based on geodesic pharmacophore

2D/3D

Pharmacophore

Screening

against

database

Screening Résults

1

2

3 Data

warehouse

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Screening animation : superposition of pharmacophores

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Scoring and analysis

Sample Hits from Screening: comparison of hit toxicity scores

Screening Strategy

:

screen a compound on a single endpoint

Screening Strategy

:

screen a compound on a several endpoints

Compound input & parameter selection

Pharmacophore screening

Scoring and analysis

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Bibliographic system

An automatically updated bibliographic system

Compound input & parameter selection

Pharmacophore screening

Scoring and analysis

Hits from the screening are cross referenced

to bibliographic entries on compounds with

similar pharmacophores.

The bibliographic references give the likely

biological context of toxicity, helping you see

the bigger picture.

You get access to the studies that have already

been published. You have decision guidance to

efficiently design any additional testing

required for the REACH dossier.

Our database can also provide basic

physico-chemical data required by REACH in the IUCLID

5 XML format.

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World’s highest level of reliability

A benchmark study against major applications on the market shows a clear advantage for MultiDIP

Actual and comparative results for this study are extracted from the following publication:

Snyder. An update on the genotoxicity and carcinogenicity of marketed pharmaceuticals with reference to

in silico

predictivity. .

Environ. Mol. Mutagen. (2009) vol. 50 (6) pp. 435-50

Sen sit ivit y: tru e p o sit ive p red ict io n s MultiDIP DEREK MC4PC 0% 20% 40% 60% 80% 100% 0% 20% 40% 60% 80% 100%

ROC Space : Mutagenicity prediction

n= 501 compounds

Specificity: false positive

157 367 501 248 -100 200 300 400 500 600 0% 20% 40% 60% 80% 100% MLA (+) In Vitro

Cytogenetics Mutagenicity Carcinogenicity

Specificity: true negatives Selectivity: true positives Nb comp.

MultiDIP Tox benchmark results ; n=556

_{Nb. tested compounds}

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Thank you

Romain GUIDON

Business Development

+33 625 14 17 66

romain.guidon@bioquanta.net

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Toxicity Screening Process

1. Pharmacophore géodésique

- technologie brevetée de modélisation

- empreinte biologique

2. Entrepôt de données

toxicologiques

- criblage virtuel

- recherche bibliographique sur les molécules

similaires

3. Expertise scientifique

- analyse et interprétation des résultats

-

rapport d’évaluation de toxicité

- signature des résultats

AIDE A LA DECISION