Reaxys rmc unified platform_ webinar_

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

2. 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

3. Putting Data to Work | 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

4. Putting Data to Work | 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 (Professional Services) In House Data Integration (RMC Flatfile) « Discoveryconnect » Data Integration of Reactions into Reaxys (Professional Services) Reaxys API/KNIME/Pipelinepilot « In silico Screening » Reaxys API/KNIME/Pipelinepilot Reaxys API/KNIME/ Pipelinepilot Reaxys API

5. 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

6. Putting Data to Work | New Information retrieval Solution at

7. Putting Data to Work | Design Philosophy at

8. Putting Data to Work | 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

9. Putting Data to Work | 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

10. Putting Data to Work | 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

12. Putting Data to Work | 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.

13. Putting Data to Work | 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

14. Putting Data to Work | 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

15. Putting Data to Work | • 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

17. 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

18. Example of Search In Reaxys using the Accelrys/Biovia ELN

19. Results in Reaxys and output to Accelrys/Biovia ELN

21. Putting Data to Work | 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

22. Putting Data to Work | 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

23. Putting Data to Work | 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

25. 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 API/KNIME/Pipelinepilot 314 Hits 39 Tested

26. 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

28. 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

29. 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. 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 ?

31. 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)

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

33. 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. | 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. | 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

37. Putting Data to Work | 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 (Professional Services) In House Data Integration (RMC Flatfile) « Discoveryconnect » Data Integration of Reactions into Reaxys (Professional Services) API/KNIME/Pipelinepilot « In silico Screening » API/KNIME/Pipelinepilot API/KNIME/ Pipelinepilot Reaxys API

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