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

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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

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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

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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

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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.

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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