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Dr. Olivier Barberan introduced us to the main features and benefits of using our medicinal chemistry database.
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1
REAXYS MEDICINAL CHEMISTRY
DR. OLIVIER BARBERAN
ELSEVIER
SEPTEMBER 2013
DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
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SITUATION: DRUG DISCOVERY
ELN
Biology
Therapeutic target
Chemistry
Check chemical feasibility
Synthesize or buy
Test
Check ADME/Tox
Report
Analyze SAR
Generate chemistry ideas
In-house
Knowledge survey
ELN
DBs
Flatfiles
Journals
Journals
Docs
Known ligands
No single solution will fit all needs, but…
DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
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Therapeutic target
Check chemical feasibility
Synthesize or buy
Test
Check ADME/Tox
Report
Analyze SAR
Generate chemistry ideas
Knowledge survey
Chemistry
In-house
ELNKnown ligands
Flatfiles
Docs
Biology
… is that really necessary?Hows about interoperability and
integration?
Wouldn’t it be nice being able to switch seamlessly between
scientific domains and find data that you have not even thought about, but would be important?
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AGENDA
Elsevier Life science Solution
Reaxys Medicinal Chemistry
Content coverage
Application in Drug discovery
QA
DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
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TARGETINSIGHTS
PHARMAPENDIUM
EMBASE QUOSA
PATHWAY STUDIO
A SUITE OF INTEROPERABLE, DOMAIN-SPECIFIC, DECISION SUPPORT TOOLSPART OF LIFE SCIENCE SOLUTIONS
TEXT MINING MEDSCAN
TAXONOMIES
(CONTENT) INTEGRATI
ON
DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
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MEDSCAN
TAXONOMIES
(CONTENT) INTEGRATI
ON
TARGETINSIGHTS
PHARMAPENDIUM
EMBASE QUOSA
PATHWAY STUDIO
REAXYS CHEMISTRY DISCOVERY ENGINE
Combines relevant chemistry information from 16,000 periodicals and over 500m experimentally validated facts with synthesis planning functionality.
REAXYS MEDICINAL CHEMISTRY
Identify, optimize and prioritize compounds with optimum affinity, selectivity and ADMET properties.
A SUITE OF INTEROPERABLE, DOMAIN-SPECIFIC, DECISION SUPPORT TOOLSPART OF LIFE SCIENCE SOLUTIONS
DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
CONTENT COVERAGE
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DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
ESSENTIAL INFORMATION: 100+ EXPERIMENTAL FIELDS
Reaxys Medicinal Chemistry excerpts all the relevant Quantitative data
DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
ESSENTIAL INFORMATION: SUPPORTING CRITICAL STAGES
IN THE DRUG DISCOVERY & DEVELOPMENT PIPELINE
9DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
COMPUTATIONAL CHEMIST (CADD*)
“I need to find hits for druggable targets” (virtual screening)
MEDICINAL CHEMIST
“I need to optimize chemical structures in order to improve affinity, selectivity ADMET properties and decrease side effects”
HIT TO LEAD
PHARMACOLOGIST
“I need to define relevant pharmacological models on animals”
LEADOPTIMIZATION
PRECLINICAL DEVELOPMENT
COMPUTATIONAL CHEMIST (CADD*)
“I need to optimize other pharmaceutical properties while maintaining affinity” (QSPR)
SYNTHETIC CHEMIST
“I need to define the easiest and most productive way to reach my target compound”
PROJECT MANAGER
“I need to be up to date with regards to competitors working on the same subjects” (Which compounds, targets are published in Journals and/or patents)
COMPUTATIONAL CHEMIST (CADD*)
“I need to optimize affinity and selectivity of hits” (Structure based design QSAR)
DISCOVERY
ESSENTIAL INFORMATION
• 2.4 M chemical compounds• 9 M biological experimental
results• 5100 Pharmacological targets
THE WORLD OF MEDICINAL CHEMISTRY AT YOUR FINGERTIPS
10DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
REAXYS MEDICINAL CHEMISTRY:THE MOST POWERFUL AND VERSATILE MEDICINAL CHEMISTRY DISCOVERY ENGINE
RELEVANT ANSWERS
• Chemistry driven searches(Substructure/Similarity)
• Pharmacology driven searches (Target, Cell, Bioassay)
• Taxonomies-driven searches
ACTIONABLE
• Intuitive and powerful user-interface
• No access barrier• Flexible export
(Manageable by user)
REAXYS MEDICINAL CHEMISTRY : PATENTS COVERAGE
Patents Origin and starting date
US : 1971-present EP : 1979-presentWO : 1978-present (English only)
Patents are coming from the A61K class mainly but not only.
Patents count : 50632
DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
REAXYS MEDICINAL CHEMISTRY : JOURNALS COVERAGE
206421 articles are included in Reaxys Medicinal Chemistry
corresponding to 1047 Journals from 1980 to present.
Some articles stored in Reaxys Medicinal Chemistry are older than 1980. 1000 articles spread between 1979 and 1941.
DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
ESSENTIAL INFORMATION
COMPOUND CHEMICAL STRUCTURE ,NAME, CODE, SYNONYM OF COMPOUND
DRUGGABLE TARGETEXPLORE TARGET AFFINITY PATTERNS OF CHEMICAL COMPOUNDS
IN VITRO AND CELL BASED ASSAYS IN VITRO ASSAYS (BINDING, SECOND MESSENGER ETC..) AND CELL BASED ASSAYS FOR EXAMPLE : AGGREGATION, ANGIOGENESIS, APOPTOSIS, CELL DIFFERENTIATION, CELLULAR CYCLE, CHONDROGENESIS
ANIMAL MODELS DISEASE OVARIECTOMIZED RAT IN OSTEOPOROSIS, TREATMENT OF GLAUCOMA, XENOGRAFTED ANIMALS WITH TUMORS TO TEST AND DEVELOP ANTINEPLASTIC DRUGS
PHARMACOKINETIC AND ADME PROPERTIESMETABOLIC STABILITY, INTRINSIC CLEARANCE, HALF LIFE OF ELIMINATION, BIOAVAILABILITY, IN VIVO CLEARANCE
TOXICITYCYTOTOXICITY, CARDIOTOXICITY, CHRONIC TOXICITY
DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
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INTERACT WITH YOUR WORKFLOW
DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
Link to full text articles
Export data in multiple formats: Text, Excel, SDF, RDF, XML files to be incorporated into third party tools
Link to Reaxys:‐ Compounds‐ Citations
Link to Embase
Link to Drug Bank
Link to Protein 3D structure: PDB
Link to Uniprot
Link to full text Patent: Espacenet
APPLICATION IN DRUG DISCOVERY
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DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
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DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
Project Kick off
Compound Library
HTS/Virtual Screening Hit to Lead Lead
Optimization
ACCESS TO KNOWLEDGE ALONG DRUG DISCOVERY CHAIN
- Focused Library- hERG Model- CYP Model
- Indications for target- Compound active on target- Most active compounds (IC50, Ki, EC50 < 50nM)- Most active competitors- Target selectivity- PK of Compounds classes- Adverse effects : CYP-blockade- Adverse effect : hERG-activity
- Calcium T Type Channel- Hit Generation : customer story- Phenotypic in silico Screening
- High affinity towards the target - Show selectivity versus targets- Reduce binding to HSA- Improve cell permeability- Not be metabolized rapidly- Not interfere with the P450 enzymes-Not interfere with the Pgp- Show selectivity versus targets (Advanced)- Multiple inhibitors : Renin angiotensin pathway
- Exploration of structural features of a lead series of Compounds-Safety pharmacology (off Targets) - Pharmacokinetics- ADMET - Computational chemistry and molecular modeling
PROJECT KICK OFF
AKT1 INHIBITORS
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DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
AKT INHIBITORS
• AKT IS ASSOCIATED WITH TUMOR CELL SURVIVAL, PROLIFERATION, AND INVASIVENESS.
• THE ACTIVATION OF AKT IS ALSO ONE OF THE MOST FREQUENT ALTERATIONS OBSERVED IN HUMAN CANCER AND TUMOR CELLS.
• Akt1 has been implicated as a major factor in many types of cancer
• Akt2 is an important signaling molecule in the Insulin signaling pathway
• The role of Akt3 is less clear, though it appears to be predominantly expressed in the brain
THEREFORE, UNDERSTANDING AKT AND ITS PATHWAYS IS IMPORTANT FOR THE CREATION OF BETTER THERAPIES TO TREAT CANCER AND TUMOR CELLS.
DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
ABOUT AKT1 INHIBITORS IN REAXYS MEDICINAL CHEMISTRY
• MOST ACTIVE COMPOUNDS ON AKT1 (IC50, KI OR KD BELOW 0.05 ΜM?)
• TARGET SELECTIVITY (AKT1 VERSUS AKT2)
• PK OF COMPOUNDS CLASSES
• ADVERSE EFFECTS : CYP-BLOCKADE
• ADVERSE EFFECT : HERG-ACTIVITY
DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
PROJECT KICK OFF
LIVE DEMO
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DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
IN SUMMARY
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DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
• Reaxys Medicinal Chemistry is a Powerful solutions across the entire Drug Discovery Workflow
• Designed to help Medicinal and Computational Chemists in all sectors, advance more quickly and confidently through their research.
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THANK YOU
QUESTIONS?
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DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
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BACKUP SLIDES
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DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
HIT GENERATION : LIGAND VIRTUAL
SCREENING CALCIUM T TYPE
CHANNEL
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DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
10/04/2023
25LABORATOIRES PIERRE FABRE 01 JUL 2011
LIGAND BASED VIRTUAL SCREENING :USING REAXYS MEDICINAL CHEMISTRY
• OBJECTIVE DESCRIBE AN IN SILICO SCREENING APPROACH USING REAXYS MEDICINAL CHEMISTRY
• CASE STUDY ON T-TYPE CALCIUM CHANNELS
DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
10/04/2023
26LABORATOIRES PIERRE FABRE 01 JUL 2011
LEADS
Hits To-LeadsIn-Silico Screening
Profiling and Qualifying LeadsHeat map approach
Pharmacology ProfileEfficacySelectivityOff Targets
HITS TO LEADS
In Silico scrrenin
g
DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
LIGAND-BASED IN SILICO SCREENINGDR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
Target Synonyms are searchable
Simple selection of parameters in the list
ANSWERS
130 compounds and 1200 experimental data
Simple Target name search returns all results
Bioassays Name Search
10/04/2023
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Representation & Chemical SpaceMolecular descriptors & Fingerprints
Virtual ScreeningPharmacophoric
Similarity
N
O
N
NN
O
N
N
N
314 Hits
DiversityDB
130 Querystructures
1. Molecular diversity and chemical originality2. Compounds availability
39 compounds ordered for testing
LIGAND-BASED IN SILICO SCREENING
"Drug-like" Filtering
DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
10/04/2023
29LABORATOIRES PIERRE FABRE 01 JUL 2011
Electrophysiology experiments : Screening @10 µM on Cav3.2 T-Type channels
9 compounds with a % inhibition > 75%15 compounds with a % Inhibition >50%
1 2 3 4 5 6 7 8 9 101112131415161718192021222324252627 29303132333435363738390
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50
75
100
Compound # (@ 10µM)
Peak c
urr
en
t in
hib
itio
n (
%)
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BIOLOGICAL ACTIVITY
CHEMICAL STRUCTURE OF ACTIVE COMPOUNDS
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Compound 18
Compound 14
Compound 20
Compound 37
Compound 35
Compound 8
Compound 17 Compound 30
Compound 32
DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER