CONFIDENTIAL INFORMATION KnowTox, a Franco- Hungarian collaborative project relative to toxicity.

CONFIDENTIAL INFORMATION

KnowTox, a Franco-Hungarian

collaborative project relative to toxicity


Overview

Aureus Pharma System

ChemAxon and Aureus Relationships

KnowTox project regarding drug-induced hepatotoxicity


Knowledge Base

Integration Platform

Query Interface

Analysis/Display Applications

The Aureus Pharma System


Aureus & ChemAxon

Business partnershipBusiness partnership

Integration of ChemAxon’s tools into our system


Cheminformatic tools integrated in AurQUEST


Aureus & ChemAxon



Aureus Aureus Research and innovation Research and innovation ProjectsProjects

Communication and Dissemination


AureusDatabase

N

O

N

O

O

O

N

N O

N

N

N

N

N

N

OO

O

N

NN

O

N

N

NH

(I)

H(I)

Representation & Chemical SpaceMolecular descriptors & Fingerprints

Virtual ScreeningPharmacophoric

Similarity

N

O

N

NN

O

N

N

N

314 Hits314 Hits

AurQuest(Biological Activity)

DiversityDiversityDBDB

45 Query45 Querystructuresstructures

Compounds Selection : 1. Molecular diversity and chemical originality2. Compounds availability38 compounds 38 compounds

ordered for ordered for testingtesting

Virtual Screening Study to Identify New T-type Calcium Channel Blockers


Preliminary electrophysiology results


Internal projects

Instant JChem

Screen

JKlustor

LibMCS (being tested)

Fragmenter (use in near future)


Aureus & ChemAxon



Aureus Aureus Research and innovation ProjectsResearch and innovation Projects

Communication and Dissemination

Collaborative Collaborative Eureka Eureka project :project :

Knowtox


Drug-induced toxicity

0

5

10

15

20

25

30

35

40

45

Clinical safety

Efficacy

Formulation

PK/Bioavailability

Commercial

Toxicology

Cost of goods

Unknown/other

1991 2000

Att

riti

on

(%

)Nature Reviews Drug Discovery 2004, 3: 711-715.

0

5

10

15

20

25

30

% o

f al

l ad

van

ced

mo

lecu

les

(n=

88)

Cardiovascular

Liver

Teratogenicity

Hematologic

CNS / PNS

RetinaM

utagenicity / clastogenicity

Reproductive toxicity

Gastrointestinal / pancreatic

Muscle

Target organ or tissue

Sites for Toxicology Attrition

Chem. Res. Toxicol. 2007, 20: 344-369.

Drugs withdrawn recently for hepatotoxicity

- Bromfenac reactive metabolite- Troglitazone reactive metabolite- Nefazodone reactive metabolite- Pemoline

Predicting drug toxicity - Bioactivation alerts - Knowledge of toxicity pathways


Predictive Toxicology European REACH (Registration, Evaluation, and

Authorization of Chemicals) system Alternative methods predictive tools in toxicology Collection of high-quality data

European work programme FP7 Theme 1 - Health

Theme 6 – Environment

Joint Technology Initiative for Innovative MedicinesInnoMed PredTox (FP6)

PREDICTING SUITABILITY, SAFETY AND EFFICACY OF THERAPIES.HEALTH-2007-1.3-1: Novel alternative testing strategies for use in pharmaceutical discovery and development.HEALTH-2007-1.3-2: Bottlenecks in reduction, refinement and replacement of animal testing in pharmaceutical discovery and development.HEALTH-2007-1.3-3: Promotion, development, validation, acceptance and implementation of QSARs (quantitative structure-activity relationship) for toxicology.HEALTH-2007-1.3-4: Alternative testing strategies for the assessment of the toxicological profile of nanoparticles used in medical diagnostics.HEALTH-2007-1.3-5: In silico modelling for ADMET outcomes.

ENVIRONMENTAL TECHNOLOGIES: TECHNOLOGY ASSESSMENT, VERIFICATION AND TESTINGENV-2007-3.3.1-1: In silico techniques for hazard-, safety-, and environmental risk-assessment.ENV-2007-3.3.1-2: Defining of a long-term research strategy for the full replacement of animal tests for repeat dose systemic toxicity.


Global Project

Knowledge base on drug-induced hepatotoxicity mined from literature

Chemical and biological liver toxicity information for reference compounds associated with ADME properties Preclinical and clinical studies Query software tool for efficient data mining and exploitation

Software tools for predicting metabolism and toxicity

Metabolite prediction Metabolic stability prediction Hepatotoxicity prediction


Define and Design database structure

Integrate literature

Provide datasets for model building

Define data needed for building the models

Identify pertinent literature Build the model

• Help to define database structure and content • Validate it

Validate predictive software tools

- sanofi-aventis- Aureus Pharma- ChemAxon/Univ. Budapest

Partners and involvement


Deliverables

New knowledgebase focused on hepatotoxicity

Database structure suitable for internal data management purpose

Metabolism prediction module

Toxicity prediction software


KnowTox database 1st version

Molecules tested as or reported as hepatoxicants Biological quantitative / qualitative in vitro or in vivo

activity Biological protocol description and details Bibliographical sources Links to external resources


Typical Queries

1. What are similar compounds to my potential hepatoxicant in term of given hepatotoxic biomarkers?

2. What are toxicological information regarding a particular chemical substructure or therapeutic class?

3. What are the histological endpoints of compounds of interest?

4. What type of cellular dysfunction injury has been described for compounds of interest?…


Ask a (chemical and / or biological) question

Retrieve biological information

AurQUEST Query software characteristics

Retrieve a list of compounds

Retrieve detailed protocols & links to bibliographical sources


Metabolizer characteristics

Metabolizer

Reactor Biotransformation library

xenobiotics

Metabolites


Toxicity prediction

Toxicity Calculator

Fragmenter EvaluatorCalculator

pluginCalculator

pluginCalculator

plugin

xenobiotics Metabolites+ stability

Toxicity data

Predicted toxicity


KnowTox Added-Value

Complete package for integration in drug discovery process

Quick search and retrieval of information Improved efficiency to manage such

undesirable events Better risk assessment (management and

anticipation) Impact on probability of success to

market new drugs


Acknowledgments

Miklos VargyasGyörgy PirokFerenc Csizmadia

György Horvai

Gilles LabbeEmmanuela AlyFrédéric Galli

François PetitetIsmaïl IjjaaliKM & IT teams


« KnowTox »

CONFIDENTIAL INFORMATION KnowTox, a Franco- Hungarian collaborative project relative to toxicity.

Documents

Transcript of CONFIDENTIAL INFORMATION KnowTox, a Franco- Hungarian collaborative project relative to toxicity.