1. Implementing chemistry platform for OpenPHACTS: Lessons learned
Colin Batchelor, Alexey Pshenichnov, Jon Steele, Valery Tkachenko
Royal Society of Chemistry
ACS Spring 2016
San Diego, CA
March 17th 2016

2. Open PHACTS Mission:
Integrate Multiple Research Biomedical Data Resources Into A Single Open & Sustainable Access Point

3. Acknowledgements Open PHACTS Practical Semantics
GlaxoSmithKline – Coordinator
Universität Wien – Managing entity
Technical University of Denmark
University of Hamburg, Center for Bioinformatics
BioSolveIT GmBH
Consorci Mar Parc de Salut de Barcelona
Leiden University Medical Centre
Royal Society of Chemistry
Vrije Universiteit Amsterdam
Novartis
Merck Serono
H. Lundbeck A/S
Eli Lilly
Netherlands Bioinformatics Centre
Swiss Institute of Bioinformatics
ConnectedDiscovery
EMBL-European Bioinformatics Institute
Janssen Esteve Almirall
OpenLink Scibite
The Open PHACTS Foundation
Spanish National Cancer Research Centre
University of Manchester
Maastricht University
Aqnowledge
University of Santiago de Compostela
Rheinische Friedrich-Wilhelms-Universität Bonn
AstraZeneca
Pfizer
@Open_PHACTS

4. Why is it so hard to…. IP? What’s the structure? Are they in our file?
What’s similar?
What’s the target?
Pharmacology data?
Known Pathways?
Working On Now?
Connections to disease?
Expressed in right cell type?
IP?
Remember this, some of these questions are easier to answer than others
Competitors?

5. How do R&D companies use public data?
Literature
PubChem
Genbank
Patents
Databases
Downloads
Data Analysis
Data Integration
Firewalled Databases
Using available public data is critical to drug discovery

6. Expanding Integration
Research Informatics
Translational Informatics
Medical Informatics (RWD)

7. Business Question Driven Approach
Number
sum
Nr of 1
Question 15 12 9
All oxidoreductase inhibitors active <100nM in both human and mouse 18 14 8
Given compound X, what is its predicted secondary pharmacology? What are the on and off,target safety concerns for a compound? What is the evidence and how reliable is that evidence (journal impact factor, KOL) for findings associated with a compound? 24 13
Given a target find me all actives against that target. Find/predict polypharmacology of actives. Determine ADMET profile of actives. 32
For a given interaction profile, give me compounds similar to it. 37
The current Factor Xa lead series is characterised by substructure X. Retrieve all bioactivity data in serine protease assays for molecules that contain substructure X. 38
Retrieve all experimental and clinical data for a given list of compounds defined by their chemical structure (with options to match stereochemistry or not). 41
A project is considering Protein Kinase C Alpha (PRKCA) as a target. What are all the compounds known to modulate the target directly? What are the compounds that may modulate the target directly? i.e. return all cmpds active in assays where the resolution is at least at the level of the target family (i.e. PKC) both from structured assay databases and the literature. 44
Give me all active compounds on a given target with the relevant assay data 46
Give me the compound(s) which hit most specifically the multiple targets in a given pathway (disease) 59
Identify all known protein-protein interaction inhibitors 10
Can go get everything
Open PHACTS not a repo of the world, specific sources

8. Mx/psa, how calculated who did it? Mash up. With your data too,
“Let me compare MW, logP and PSA for known oxidoreductase inhibitors”
“What is the selectivity profile of known p38 inhibitors?”
“Find me compounds that inhibit targets in NFkB pathway assayed in only functional assays with a potency <1 μM”
ChEMBL
DrugBank
Gene Ontology
Wikipathways
GeneGo
Open PHACTS was developed to support the key questions of drug discovery
Business questions have been at the heart of Open PHACTS and have driven the development of the platform
Mx/psa, how calculated who did it?
Mash up. With your data too,
- top layer join together but need them all
commercial
ChEBI
UniProt
UMLS
neXtProt
GVKBio
ConceptWiki
ChemSpider
DisGeNet
TrialTrove
TR Integrity
ChEMBL
Target Class
ENZYME
FDA adverse
events
SureChEMBL 8

9. Open PHACTS was developed to support the key questions of drug discovery
Business questions have been at the heart of Open PHACTS and have driven the development of the platform
Mx/psa, how calculated who did it?
Mash up. With your data too,
- top layer join together but need them all
commercial
Data provided by many publishers
Originally in many formats: relational, SD files and RDF
Worked closely with publishers
Data licensing was a major issue
Over 5 billion triples – 14 datasets & growing
Hosted on beefy hardware; data in memory (aim)
Extensive memcaching
Pose complex queries to extract data
@gray_alasdair
Big Data Integration

10. Patent annotations in Open PHACTS
Huge amount of knowledge hidden in patent corpus
Most of which will never be published elsewhere
Substantial lag between patent and scientific literature
SureChEMBL system already extracts chemical entities from full-text patent documents
Text (title, abstract, description, claims), images, molfiles
Complemented with gene and disease entity annotations
Using the Termite text-mining tool by SciBite
Relevance scoring to reduce noise
Tested for recall
Patent, compound, gene, disease info available via API
4 million full-text patent documents annotated
• USPTO, WIPO, EPO – English language
• Life-sciences relevant
• Patents mapped to SureChEMBL IDs (e.g. EP A2)
• Title, publication date, classification codes
• Compounds mapped to SCHEMBL IDs (e.g. SCHEMBL15064)
• Genes mapped to HGNC symbols (e.g. FDFT1)
• Diseases mapped to MeSH terms (e.g. D009765)

11. Open PHACTS Expanding EcoSystem
Data Warrior
Further Apps Db
Stds :which ones (later)
Access (API). Driven by the API. Acelerate bulding if apps

12. Want to run Open PHACTS within your environment?
Want to load your data into Open PHACTS?
VM install of Open PHACTS
Docker Image is now available
Updating to ver 2.0 Open PHACTS
Allows you to customise and load your own data into the environment

13. Open PHACTS discover platform is now supported by a Foundation

14. Usage >500 million queries
Seen a growing usage of the platform both in volume and in registered applications
API remains the cornerstone of the delivery

15. All Users by Sector Type
Connected to different consumer groups

16. Upgrading Challenge of migrating between versions of the API
Once users get connected to an API, they tend to stick with it.
We are listening to this and will have a version independent URL
Upgrading

18. Explorer Explorer2 ChemBioNavigator Target Dossier Pharmatrek Helium
MOE Collector Cytophacts Utopia Garfield SciBite
KNIME Mol. Data Sheets PipelinePilot scinav.it Taverna

19. Explorer.openphacts.org
openphactsfoundation.org/apps.html

20.
Here we see the RSC dataset in Open PHACT’s data repository, which is running the open source Artifactory.
The repository understands Maven metadata, and also maintain and verifies checksums of data artifacts.
We see here it includes the suggested <dependency> setting for using the dataset from a different Maven project – while this would be a bit exotic perhaps, doing so would put the dataset directly on the classloader without any worrying about downloads or file paths.
We can see the hierarchy of the dataset on the left – the repository has expanded the archive for us. The .ro folder contains the Research Object manifest, the void file is the Dataset description – the rest is the “actual data”.
One power of Maven is the ease of setting up mirroring – the dataset above is actually from a mirror of the Maven repository of the build server in Manchester.

21. Apps Linked Data API (RDF/XML, TTL, JSON) Data Cache RDF RDF RDF RDF
Identity Resolution
Service
Linked Data API (RDF/XML, TTL, JSON)
“Adenosine receptor 2a”
Domain
Specific
Services
Semantic Workflow Engine
Identifier
Management
Service
P12374
Core Platform
EC2.43.4
CS4532
Data Cache
(Virtuoso Triple Store)
Chemistry Registration
Normalisation & Q/C
All have probably seen this slide.
Want to pick out some of the key changes and tomorrow will here more
Indexing
VoID
VoID
VoID
VoID
VoID
RDF
RDF
Nanopub
Nanopub
Nanopub
RDF
RDF
RDF
Public Ontologies Db Db Db Db
User
Annotations
Public Content
Commercial

22. The Royal Society of Chemistry’s role in Open PHACTS
We integrate, standardize and host the chemical compound collection underpinning Open PHACTS.
We have developed a structure validation and normalization platform (CVSP) to ensure chemical structures are normalized to rules derived from the FDA structure normalization guidelines and modified based on input from members of EFPIA.

23. CVSP and the Open Pharmacological Space Chemical Registration System (OPS CRS)
Freely-available (requires logging in) chemical validation system for:
Structure validation: warning on query atoms, pseudoatoms, nonsensical or unclear stereo
Standardization workflows.

24. Chemical data sources Data source Number of records in source DrugBank
6828
PDB ligands
18681
MeSH (extracted by text mining)
24381
ChEBI
40503
HMDB
41494
ChEMBL 20
SureChEMBL 1.0

25. Royal Society of Chemistry data provided to Open PHACTS
We generate RDF that:
Describes synonyms and identifiers
Provides linksets between our data sources and the OPS identifiers
Describes molecule–molecule relations of interest to the pharma industry
Delivers calculated physicochemical properties of compounds
Lists the validation and standardization issues found by CVSP.

26. Principles
Use standard ontologies where possible (CHEMINF for cheminformatics properties, QUDT for units, OBO ontologies elsewhere)
Use an event-based pattern for cheminformatics outputs. This enables us to add arbitrary provenance information.

27. 1. Synonyms and identifiers
Use the CHEMINF ontology:
Validated ChemSpider synonyms, Unvalidated ChemSpider synonyms, Validated database identifiers, Unvalidated database identifiers, InChI, InChIKey, SMILES, preferred ChemSpider name

28. 2. Linksets: Vocabulary of Interlinked Datasets
Metadata describing the RDF:
Can be used to build a directory of the RDF available
Find what’s there without having to download all of it first
Describes how Datasets are linked by the Linksets using SKOS.
Recommendations here:

29. 3. Molecule–molecule relations in CHEMINF
We relate molecules to “parent” forms, variously, those which are:
uncharged
not isotopically-specified
not stereochemically-specified
the preferred tautomer
the largest fragment
the “superparent” (all of the above)

30. 4. Calculated physicochemical properties
log P, log D (at pH 5.5 and 7.4), bioconcentration factor, KOC (at pH 5.5 and 7.4), index of refraction, polar surface area, molar refractivity, molar volume, polarizability, surface tension, density at STP, flash point a 1 atm, enthalpy of vaporization at STP, vapour pressure at STP.

31. 5. Issues from validation and standardization
We use the CHEMINF ontology again.
We distinguish between information, warnings and errors. Only serious failures to process, such as a structure having an invalid atom, count as errors.

32. This is the world we live in

33. Data quality issue and CVSP
Robochemistry
Proliferation of errors in public and private databases
ChemSpider
PubChem
DrugBank
KEGG
ChEBI/ChEMBL
Automated quality control system

34. Chemistry Validation and Standardization Platform

35. Chemistry Validation and Standardization Platform

36. Thank you
Slides: 36