Reaxys rmc unified platform_ webinar_

How do you handle data
from multiple chemistry
sources?
Find out how Reaxys
made it easier
June 2016
o.barberan@elsevier.com
Olivier Barberan

Putting Data to Work |
Data-driven drug design and research
2
• General descriptor-property
relationships
• Sub-structural alerts
• QSAR
• Matched Molecular Pair
analyses
• Predictive pharmacology
Etc…
Cumming, J.G., Davis, A.M. et al. Nat. Rev. Drug Disc. (2013) 12, 948–962
Data Knowledge
Analysis
Predictions
• Data normalization
• Taxonomies
• Quality control
Etc…
“Those who cannot remember the past are condemned to repeat it.”
George Santayana: Life of Reason, Reason in Common Sense, Scribner's, 1905, page 284
ELSEVIER

Transforms Data and Knowledge to Real Research
 Select the right compounds, active to right targets for right patients
 Stay tuned for advanced research and competitor’s work
 Access data, interpret data, act on data for incisive decision

Reaxys Provides a Unified Information Portal
•Provides a single
powerful interface
•Can integrate several
notebook systems
•Links chemistry,
structures, sourcing,
citations, and full-text
of articles
Reaxys
API/KNIME/Pipelinepilot
(Professional Services)
« Self service »
Data
Integration into Reaxys
In House Data
Integration (RMC Flatfile)
« Discoveryconnect »
Data Integration of
Reactions into Reaxys
Reaxys
« In silico Screening »
Reaxys
Reaxys
API/KNIME/
Pipelinepilot
Reaxys API

Putting Data to Work | | 5
The current information retrieval solution at
Project chemists & modelers
Questions:
• Any Information
for my target?
• Any compounds
similar to my
ligand
• Any new MOA
for my disease?
Output:
• Manual collected
customized file
• Up-to-search date
data
• Multi-sources
Take days to
weeks
Expert searchers
Where Science Intersects with Business – Creating
Business Dashboards That Combine Data from
Multiple Sources
Presented at Bioit World 2015 by H. Wang,E. Gifford,
M. Clark

New Information retrieval Solution at

Design Philosophy at

Reaxys/RMC KNIME and Pipeline pilot new nodes
- 4 new KNIME nodes and Pipeline pilot components are available
- Covering Bioactivities, Citations, Reactions and Substances searches
- API Access is needed to use Reaxys/RMC KNIME and Pipeline piltot Nodes
Reaxys KNIME Nodes are compatible with
Version 2.12 and 3.1x - Reaxys PP Nodes are compatible with
Version 9.5

Summarize Latest Information (Patents, Articles) about Cancer using
Reaxys and RMC API and Pipeline pilot
Latest Patents, journal
articles, compounds,
reactions related to
• Target
• Indication
• Compound
Summary of new Data for last 30 days

Compound Assays for a Given Target (p38b) using RMC API and
Pipeline pilot
Lists assays, results, assay details
• Enhance with clustering by structure
• Include in-house information

Roche : Business Case
 What - Improve efficiency of research.
Synthesis planning
Publication authorship
Patent submission
 Why - Save time and money.
Short-term spend, long-term benefit
 How - Reduce user interfaces and eliminate slow software.
Decommission ISIS/Host, circumvent ELN search
 Who - A highly functional collaboration.
Arcondis Group
Elsevier Information Systems GmbH
F. Hoffmann-La Roche
NextMove Software Ltd.

Electronic Lab
Notebooks
Data Capture,
Normalization and
Integration
Reaxys
Data
Unified
discovery
interface for
researchers
Challenge: Chemistry information is housed in separate databases, leading to inefficient research and
escalating costs. Need integration of data to accelerate research and increase discoverability.
Roche Challenge

https://reaxys.roche.com
Normalized
Roche-specific
reaction data
Data on references
and/or experiments,
including PDF links
Roche-specific data is included in the
Output (PDF, MS-Word etc.)
Filters on Roche-
specific data
fields
Up to four Roche reaction data
sources are supported

• Customer Feedback
Integration of Roche in-house data
• Usability and acceptance tests by
Roche showed:
• Increased productivity of researchers at
Roche
• Increased discoverability of the Roche
reaction content
• Reduced maintenance effort for Roche:
• Legacy systems were decommissioned
• Roche gets on-going maintenance and
functionality improvements by Elsevier
• Not compromise in security
• Several advantages of going for an
implementation of the flexible approach:
• Additional data sources have been added

Reaxys – Electronic Lab Notebook interoperability
 The Reaxys team currently works in partnership with three major ELN providers:
PerkinElmer (formerly CambridgeSoft), Accelrys/biovia and IDBS
Run query from within
the ELN
Import reaction or
substance
Browse, navigate and
refine in Reaxys
Select and export

Example of Search In Reaxys using the Accelrys/Biovia
ELN

Results in Reaxys and output to Accelrys/Biovia ELN

Integrating E-notebook data with published data
• E-notebooks are an important
mechanism to capture
intellectual property
• Not optimized for data
exploration
• Reaxys interface is optimized
for data retrieval
• Filtering
• Cross-linking
• Search trail
• Links to source full-text
21

Integration of assay data
• E-notebooks are primary
data storage
• Have only internally-
generated data
• Integration allows access to
“all known data” with one
search
• Link structures and data
• Handles target name
synonyms
22

Integrated Solution Search
23
List of integrated
sources
Sources list can include licensed
databases, and multiple e-notebooks
from organizational units
All e-notebooks can be integrated and
searched together

Ligand Based virtual Screening to Identify New T-Type Calcium
Channel blockers (Cav3.2)
Objective : Describe an In Silico Screening approach using Reaxys Medicinal Chemistry
(API and Flatfile) to identify new T-Type Calcium Channel blockers
130 Active compounds
on Cav 3.2 (affinity <0.1 µM)
Flat file
Representation & Chemical
Space Molecular descriptors &
Fingerprints
Virtual Screening
Pharmacophoric Similarity
N
O
N
N
N
O
N
N
N
"Drug-like" Filtering
1. Molecular diversity and chemical originality
2. Compounds availability
1
2
3
4
5
1) Searching for Active Compounds on Cav3.2 ( affinity < 0.1µM)
Channel in Reaxys Medicinal Chemistry Using KNIME/Pipeline pilot
2) Build a pharmacophoric similarity Model based on Active
compounds found in RMC
3) Use of the Reaxys Flat file as an External Chemical source
4) Drug like filtering of potential Cav3,2 blockers
5) Biological testing on Cav3.2
314 Hits
39 Tested

26
Biological testing of the 39 Hits on Cav3.2
Electrophysiology experiments: Screening @10
µM on Cav3.2 T-Type channels
1 2 3 4 5 6 7 8 9 101112131415161718192021222324252627 2930313233343536373839
0
25
50
75
100
Peakcurrentinhibition(%)
28
9 compounds with a % inhibition > 75%
15 compounds with a % inhibition >50%
Compound # (@ 10µM)
Reaxys medicinal chemistry supports Ligand based virtual
Screening approaches

Target-directed and Phenotypic screening: parallel pathways to the
same goal
Phenotypic screening identifies compounds
that produce a biological response in a cell
or animal model
Target screening identifies
compounds that produce a biological
response on an isolated target

Phenotype - led vs. Target - led
However, a drawback is the need to use time-consuming genetic, chemical and/or
biophysical methods to identify the targets of compounds that are active (Target
deconvolution)
Phenotypic screening can find molecules that have more optimized drug-like
properties (such as cell penetration) than target-based screens.

30
Scenario
Melanoma cells predominantly occur in skin. Melanoma is less common than
other skin cancer. However, it is much more dangerous if it is not found in the
early stages. It causes the majority (75%) of deaths related to skin cancer.
Which are the targets involved in proliferation of melanoma cells lines ? And
which substances are acting on ?
Melanoma Cells
Search In RMC
Which Targets are involved in melanoma cells proliferation ?

Target Fingerprint of A 375 Melanoma cells based on Similar Compounds
996
molecules
Cell line A375
IC50 <= 1µM
3525 molecules
+In vitro Biological
results on targets
In vitro Biological
results on targets
Define activity class of
compounds
active / inactive on target
Target active
ratio calculation
3525
molecules
Chemical Similarity
Search 85%
For each compound and its given target:
Compound_Active_Ratio = (#Actives) / (#Actives +
#Inactives)
Active if Active_Ratio ≥ 0.8
Inactive if Active_Ratio ≤ 0.2
For each Target, count the number of Active and Inactive
molecules
Target_Active_Ratio = (#Actives - #Inactives) / (#Actives
+ #Inactives)

Target Fingeprint of A375 based on similar Compounds
(85% similarity)
#Molecules >= 20
Average Activity
Rate in RMC

Key Take Away
Using Reaxys API and Pipeline pilot an automated process was set up to
establish a target FingerPrint for disease specific cell lines.
Reaxys Medicinal chemistry provides High Quality data to identify
pharmacological targets involved in phenotypic screening and understand the
molecular mechanisms of action of drugs (MMOA).

| 35
Customer problem
• In drug development, we need to screen large chemical libraries to identify
compounds with desired properties
• Instead of experimentally testing all compounds, an in-silico pre-screening is
usually performed
• For the in-silico pre-screening process, we need to have powerful predictive
models in hand
• Such models are constructed using experimentally derived data
The Elsevier solution
• Reaxys is the most comprehensive source for experientally derived
information on chemical compounds
• This information can be used to construct high-performance predictive
models
• The best way to retrieve the required information from Reaxys is using the
Reaxys API which can be accessed from Knime or PipelinePilot
• Elsevier provides readily usable Knime and PipelinePilot components
Your problem… and our solution

| 36
Building a QSAR model for α-Chymotrypsin activity
Using KNIME
For training the
model, we retrieved
~ 5.000 quantitative
bioactivity data
points for “Alpha
Chymotrypsin”
extracted from RMC
using the API
With an error rate of
0.2 the model
predicts for new
compounds if they
are active or not

Reaxys Provides a Unified Information Portal
•Provides a single
powerful interface
•Can integrate several
notebook systems
•Links chemistry,
structures, sourcing,
citations, and full-text
of articles
Reaxys
« Self service »
Data
Integration into Reaxys
In House Data
Integration (RMC Flatfile)
« Discoveryconnect »
Data Integration of
Reactions into Reaxys
« In silico Screening »
API/KNIME/
Pipelinepilot
Reaxys API

Reaxys rmc unified platform_ webinar_

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