Dr. Olivier Barberan introduced us to the main features and benefits of using our medicinal chemistry database.

1. REAXYS MEDICINAL
CHEMISTRY
DR. OLIVIER BARBERAN
ELSEVIER
SEPTEMBER 2013
DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
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2. 2
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

3. 3
Therapeutic
target
Check chemical
feasibility
Synthesize
or buy
Test
Check
ADME/Tox
Report
Analyze
SAR
Generate
chemistry ideas
Knowledge
survey
Chemistry
In-house
ELN
Known 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?

4. AGENDA
Elsevier Life science Solution
Reaxys Medicinal Chemistry
Content coverage
Application in Drug discovery
QA
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DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER

5. TARGETINSIGHTS
PHARMAPENDIUM
EMBASE QUOSA
PATHWAY STUDIO
A SUITE OF INTEROPERABLE, DOMAIN-SPECIFIC, DECISION SUPPORT TOOLS
PART OF LIFE SCIENCE SOLUTIONS
5
TEXT MINING MEDSCAN
TAXONOMIES
(CONTENT)
INTEGRATION
DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER

6. MEDSCAN
TAXONOMIES
(CONTENT)
INTEGRATION
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 TOOLS
PART OF LIFE SCIENCE SOLUTIONS
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7. CONTENT COVERAGE
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8. ESSENTIAL INFORMATION: 100+ EXPERIMENTAL FIELDS
Reaxys Medicinal Chemistry excerpts all the relevant Quantitative data
DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER

9. ESSENTIAL INFORMATION: SUPPORTING CRITICAL STAGES
IN THE DRUG DISCOVERY & DEVELOPMENT PIPELINE
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DR. 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”
LEAD
OPTIMIZATION
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

10. ESSENTIAL INFORMATION
• 2.4 M chemical compounds
• 9 M biological experimental results
• 5100 Pharmacological targets
THE WORLD OF MEDICINAL CHEMISTRY AT YOUR FINGERTIPS
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DR. 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)

11. REAXYS MEDICINAL CHEMISTRY : PATENTS COVERAGE
Patents Origin and starting date
US : 1971-present
EP : 1979-present
WO : 1978-present (English only)
Patents are coming from the A61K class
mainly but not only.
Patents count : 50632
DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER

12. 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

13. ESSENTIAL INFORMATION
COMPOUND
CHEMICAL STRUCTURE ,NAME, CODE, SYNONYM OF COMPOUND
DRUGGABLE TARGET
EXPLORE 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 PROPERTIES
METABOLIC STABILITY, INTRINSIC CLEARANCE, HALF LIFE OF ELIMINATION, BIOAVAILABILITY, IN VIVO CLEARANCE
TOXICITY
CYTOTOXICITY, CARDIOTOXICITY, CHRONIC TOXICITY
DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER

14. INTERACT WITH YOUR WORKFLOW
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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

15. APPLICATION IN DRUG
DISCOVERY
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16. DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER
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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

17. PROJECT KICK OFF
AKT1 INHIBITORS
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DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER

18. 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

19. 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

20. PROJECT KICK OFF
LIVE DEMO
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21. 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.

22. 22
THANK YOU
QUESTIONS?
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23. 23
BACKUP SLIDES
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24. HIT GENERATION : LIGAND
VIRTUAL SCREENING
CALCIUM T TYPE CHANNEL
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25. LIGAND BASED VIRTUAL SCREENING :
USING REAXYS MEDICINAL CHEMISTRY
01/10/201
3
25
LABORATOIRES PIERRE FABRE 01 JUL
2011
• OBJECTIVE
DESCRIBE AN IN SILICO SCREENING APPROACH
USING REAXYS MEDICINAL CHEMISTRY
• CASE STUDY ON T-TYPE CALCIUM CHANNELS
DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER

26. 01/10/201
3
26
LABORATOIRES PIERRE FABRE 01 JUL
2011
LEADS
Hits To-Leads
In-Silico Screening
Profiling and Qualifying Leads
Heat map approach
Pharmacology
Profile
Efficacy
Selectivity
Off Targets
HITS TO LEADS
In Silico
scrrening
DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER

27. LIGAND-BASED IN SILICO SCREENING
DR. 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

28. 01/10/201
3
28
Representation & Chemical Space
Molecular descriptors & Fingerprints
Virtual Screening
Pharmacophoric Similarity
N
O
N
N
N
O
N
N
N
314 Hits
Diversity
DB
130 Query
structures
1. Molecular diversity and chemical originality
2. Compounds availability
39 compounds ordered for testing
LIGAND-BASED IN SILICO SCREENING
"Drug-like"
Filtering
DR. OLIVIER BARBERAN | SEPTEMBER 2013| ELSEVIER

29. 01/10/201
3
29
Electrophysiology experiments :
Screening @10 µM on Cav3.2 T-Type channels
9 compounds with a % inhibition > 75%
15 compounds with a % Inhibition >50%
LABORATOIRES PIERRE FABRE 01 JUL
2011
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 29 30 31 32 33 34 35 36 37 38 39
0
25
50
75
100
Compound # (@ 10µM)
Peakcurrentinhibition(%)
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BIOLOGICAL ACTIVITY

30. 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