Post on 28-Jan-2016
description
The Open Pharmacological Concepts Triple Store
www.openphacts.org
The Innovative Medicines Initiative– EC funded public-private partnership for
pharmaceutical research– Focus on key problems
• Efficacy• Safety• Education & Training• Knowledge Management
www.openphacts.org
Public Domain is engaging in Drug Discovery (DD)Public Domain Chemistry Resources are improving
– NIH Roadmap Initiative• Molecular Library Screening Center
Network (MLSCN)• PubChem (structure, bioassay and
bioactivity data).
– DrugBank, ChEBI, ChemBank and Chembl.
Databases supporting biology-based DD are less apparent
– Rich public domain resources for biology are not DD-centric
20082006
Pharma Companies spend over $50 billion p.a. on R&DHow much of this knowledge/information is in the public domain?How much knowledge is tacit? e.g. druggability?How much is truly competitive?
Sorel Muresan, Peter Varkonyi, Chris Southan
Open PHACTS Project aims to
Develop a set of robust standards…
Implement the standards in a semantic integration hub (“Open Pharmacological Space”)…
Deliver services to support on-going drug discovery programs in pharma and public domain…
Guiding principle is open access, open usage, open source- Key to standards adoption -
Guiding principle is open access, open usage, open source- Key to standards adoption -
www.openphacts.org
OPS Services should allow to
integrate data on target expression, biological pathways and pharmacology to identify the most productive points for therapeutic intervention
investigate the in vitro pharmacology and mode-of-action of novel targets to help develop screening assays for drug discovery programmes
compare molecular interaction profiles to assess potential off-target effects and safety pharmacology
analyse chemical motifs against biological effects to deconvolute high content biology assays
www.openphacts.org
Major Work Streams:
• “Build”: OPS service layer and resource integration
• “Drive”: Development of exemplar work packages & Applications
• ”Sustain”: Community engagement and long-term sustainability
Assertion & Meta Data MgmtTransform / TranslateIntegrator
OPS Service Layer
Corpus 1
‘Consumer’Firewall
SupplierFirewall
Db 2
Db 3
Db 4
Corpus 5
Std PublicVocabularies
TargetDossier
CompoundDossier
PharmacologicalNetworks
BusinessRules
Work Stream 1: Open Pharmacological Space (OPS) Service LayerStandardised software layer to allow public DD resource integration− Define standards and construct OPS service layer− Develop interface (API) for data access, integration
and analysis− Develop secure access models
Existing Drug Discovery (DD) Resource Integration
Work Stream 2: Exemplar Drug Discovery Informatics toolsDevelop exemplar services to test OPS Service Layer Target Dossier (Data Integration)Pharmacological Network Navigator (Data Visualisation)Compound Dossier (Data Analysis)
Open PHACTS follows a use case driven approach
Main architecture, technical implementation and primary capabilities are driven by a set of prioritised research questions
Based on the main research questions, prioritised data sources are defined
Three Exemplars will be developed to demonstrate the capabilites of the OPS System and to define interfaces and input/output standards
Three Use cases have been defined to benchmark the OPS system towards current standard workflows in data retrieval and mining
Milestone 1 (month 1)
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Research questions– Give all compounds with IC50 < xxx for target Y in species W and Z plus assay data
– What substructures are associated with readout X (target, pathway, disease, …)
– Give all experimental and clinical data for compound X
– Give all targets for compound X or a compound with a similarity > y%
Exemplar Services – Chem-Bio Navigator: querying and visualization of sets of pharmacologically annotated
small molecules, on basis of chemical substructures, pharmacophores, biological activities
– Target Dossier: in silico dossiers about targets, incorporating related information on sequences, structures, pathways, diseases and small molecules
– Polypharmacology Browser: map coverage of the chemo-biological space, to facilitate the polypharmacological profiling of small molecules
Drug Discovery Pilots/Case Studies– Fusion/aggregation of data from different domains to improve predictions of drug-transporter
interactions
– Combine physicochemical data and data from transporter interaction for prediction of blood-brain barrier permeation and tissue distribution
– Target validation work-bench: in silico target validation studies
www.openphacts.org
Prioritised Research Questions
Number sum Nr of 1 Question
15 12 9 All oxido,reductase inhibitors active <100nM in both human and mouse
18 14 8Given 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 8Given a target find me all actives against that target. Find/predict polypharmacology of actives. Determine ADMET profile of actives.
32 13 8 For a given interaction profile, give me compounds similar to it.
37 13 8The 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 13 8Retrieve all experimental and clinical data for a given list of compounds defined by their chemical structure (with options to match stereochemistry or not).
41 13 8
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 13 8 Give me all active compounds on a given target with the relevant assay data46 13 8 Give me the compound(s) which hit most specifically the multiple targets in a given pathway (disease)59 14 8 Identify all known protein-protein interaction inhibitors
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Prioritised Research Questions
Prevalent Concepts– Compound
– Bioassay
– Target
– Pathway
– Disease
Prevalent data relationships– Compound – target
– Compound – bioassay
– Bioassay – target
– Compound – target – mode of action
– Target – target classification
– Target – pathway
– Target – disease
– Pathway - disease
Required cheminformatics functionality– Chemical substructure searching– Chemical similarity searching
Required bioinformatics functionalitySequence and similarity searching
Bioprofile similarity searching
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Selection of prioritised data sources
Chemistry– Chembl (top)
– DrugBank
– Chebi
– Wombat (commercial)
– Pubchem
– Chemspider
– Human Metabolome DB
Ontologies– AmiGo
– KEGG
– OBI
– Bioassay
– EFO
Biology– EntrezGene– HGNC– Uniprot– Interpro– SCOP– Wikipathway– OMIM– IUPHAR
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Nanopublications – Capturing scientific information in the Triple Store
Characteristics:
• Produce a working system (not a mockup)
• Constrained to use technologies present now in the consortium and a few data sources
• Focused on two prioritized research questions (Q15 and Q30)• Q 15: All oxidoreductase inhibitors active <100nM in both human and mouse• Q 30: For a given compound [clozapine], give me the interaction profile with
[human or mouse] targets
• Minimum requirements: two data sources (one targets, one compounds) and able to produce answers in “manual time”
Second milestone: Deliver a working prototype of “Open Pharmacological Space” in 6 months using established technology
www.openphacts.org
Build the prototype:
Uri mapping
ChEMBL ScaiView Index
ConceptWiki
ConceptWikiUI
BridgeDB
WikiPathways
PathPhysio
UtopiaDocs
LinkedLifeData
ConceptWiki
ChemSpider
LarKC
LinkedOpen
DrugData
Other mappings
Term mapping
User Interfacesoftware
Identity ResolutionService
Distributed system
LarKC in the core
SPARQL or LarKC plugin
IRS to disambiguate
Data sources
SPARQL
Expected outcomes of this exercise:
• Team building
• Performance / scalability analysis
• Does it provide an adequate answer to the research questions 15 and 30?
• Demo for users (drive group) to recalibrate build tasks in order to better respond to user requirements
www.openphacts.org
Developers(Builders)
End users(Drivers)
The three Exemplars:• Target dossier • Chem/bio space navigator • Polypharmacology browser
The Apps must provide answers to relevant research questions
• Interrogation model• GUI/interactivity• Presentation of results
Use the prototype: Connection with user needs - Exemplars
GUI - User suggestions for workflow
Select question (“template”
from category)
Fill in template variablesVia “relation browser”
and add filters(IC50 value, dates etc)
View results, filter andexport dataset
Select relevantdata sources
Execute searchModify query
(change conceptsand attributes)
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Chem-Bio-Navigator (BioSolveIT / UHH)
• Compound centric view:
Overall aim: Mixing Cheminformatics with RDF data accessM. Rarey / C. Lemmen
Data objects
Usecases
Systemarchitecture
User interface designResearch
Questions
N
N NH2
NH2
OMe
MeO
MeO
Intuitive Browsing • single molecules• molecular setsGraphical annotation• 2D / 3D?Powerful data selection
Benchmarking approach for the Target Dossier
Target dossier (CNIO)
www.openphacts.org
Polypharmacology browser (DTU)From WP4 data stored
Annotation Prediction
PPI
Chem
ical
cent
ricTa
rget
cent
ric
- Disease(s) – gene(s)- Tissue specificity- Gene ontology, side effects
based on:- Chemical structure similarity- Chemical bioactivity similarity- Proteins promiscuity
Polypharmacology browser (PSMAR)
Quick Summary of the Open PHACTS project
Develop a set of robust standards to enable:
– Solid integration between data sources via semantic technologies
– Development of high quality assertions
– Workflows and analysis pipelines across resources
Implement the standards in a semantic integration hub (“Open Pharmacological Space”)
– The core of the OPS call is to develop an open, public domain infrastructure for drug discovery data integration
– Development of open web-services* for drug discovery
– Development of a secure access model to enable queries with proprietary data (pharma, SME, NGO and PPP)
Deliver services to support on-going drug discovery programs in pharma and public domain
– Align development of standards, vocabs and data integration to selected drug discovery issues
– Ensure focus and aligned priorities within Open PHACTS project
Guiding principle is open access, open usage, open source- Key to standards adoption -
Guiding principle is open access, open usage, open source- Key to standards adoption -
Open PHACTS Governance
Success Factors
The ability of the platform to provide answers to drug discovery related questions and to be an integrated part of the drug-discovery workflow.
Measurable use of the system beyond the original OPS partners, not only for direct knowledge discovery but also as a framework to build and deliver a wide range of services.
OPS should grow to acceptable levels of quality, performance, usability and completeness and should be easily accessible and extendable within the scope of the project as a reliable enterprise system.
Early community adoption through the engagement of 'associated partners' within and outside the European Union, among which are major data and infrastructure providers and networked initiatives
Commercial information supply chain companies deliver data through and build services on top of OPS platform.
www.openphacts.org
Open PHACTS Project Partners
Pfizer Limited – 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
Spanish National Cancer Research Centre
University of Manchester
Maastricht University
Aqnowledge
University of Santiago de Compostela
Rheinische Friedrich-Wilhelms-Universität Bonn
AstraZeneca
GlaxoSmithKline
Esteve
Novartis
Merck Serono
H. Lundbeck A/S
Eli LillyNetherlands Bioinformatics CentreSwiss Institute of BioinformaticsConnectedDiscoveryEMBL-European Bioinformatics Institute
Janssen Pharmaceutica
OpenLink
The Open PHACTS Foundation
www.openphacts.org