Download The Molecular Drug Target Standard

Son of Standardizing
Drug Target Types
A Pistoia Vocabulary Standard Initiative
Lee Harland, Christopher Larminie
And Phoebe Roberts
With input from the Pistoia VSI group
Was a PUBLIC DOCUMENT
Drug Targets
• A ‘simple’ monomer? – HTR1B
(or 5ht-1b, 5ht1b, htr1b…etc)
• A ‘stable’ (core) complex – 2(NR1:NR2A)
• A ‘dynamic’ complex – NMDA-MASC
What is the
“target” of
insulin?
From: A. J. Pocklington, J. D. Armstrong and S. G. N. Grant
(2006): Organization of brain complexity — synapse
proteome form and function. Briefings in Functional
Genomics and Prot 5(1), pp66-73
Example from a pipeline database
• Research programme: Wnt signalling
pathway inhibitors
• Three proprietary drug targets which
inhibit the Wnt pathway have been
identified by the company. The
company's most advanced candidates
inhibit the interaction between Bcl9/hLgs
and beta-catenin, the key regulatory
protein in Wnt-signal transduction
Problem Statement
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No agreed standard for representing a Molecular
Drug Target within information systems. ad hoc
solutions, often free text or simple list of gene
identifiers.
Especially for non-single protein entities (see
right)
Crucially, no public URI to link identical concepts
across different sources. For instance “Protein
Kinase C”
Effect: No mechanism for association of data
between crucial drug discovery entities
More than a “vocabulary” issue – its how a target
should be represented
A molecular drug target standard could accomplish
3 things:
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Represent: A common scheme to describe a drug
target.
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Including URIs for all known drug targets(*)
Organise: Map all known drug targets to a
pharmacologically relevant taxonomy
Discover: Exploit the resource to identify assertions
relating to drug target concepts
http://dx.doi.org/10.1517/17460440903049290
High Level Summary
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Representation of a molecular drug target in structured databases is ad-hoc
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This project will focus on industry & suppliers to describe a specification for reporting
drug targets within structured content
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Single protein-targets are “OK” (being linked via Entrez gene, but this is not an agreed standard)
Multi-protein targets, complexes, biologicals and many more are poorly described, often simply
raw text
Minimal cost, just FTE time required
This could feed into the IMI Open Pharmacology (OPS) call as an industry-publisher requirement
Output would be a specific set of “rules” regarding the representation of complex molecular
targets
Aim would not be to define a list of all known targets, this would be out of scope. As will any
text-mining efforts.
Recommendation to suppliers and industry to adopt specification along with industry-generated
mappings for pre-existing targets
Deliverable – specification & publication
Could be a start to a future, wider phamacological data standard project
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All databases providing pharmacological activity content delivered in a standard way
Could gain a quick-start building on MIABE standard
Definitions
• Target Form ontology:
– A small list of TYPES/FORMS/ROLES that a drug target can be.
E.g. single protein, protein complex, fuzzy group etc
• Target Instance ontology:
– An ontology representing the targets themselves, providing a
URI for things such as Protein Kinase C, NMDA Receptor etc
• Target Family ontology:
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An ontology grouping together different targets under the
same functional property, e.g. “Aminergic Receptors”, “Serine
Proteases”, “Phosphodiesterases”
This first phase of the Target Standard project will look to
define the Target Form ontology ONLY.
Other things we need to say about a
drug and its target
• What the drug is doing to the activity of the
target (a.k.a. “mode of action”)
– inhibiting, activating, or mimicking?
– This is relatively well standardized, not an
impediment to use and integration
• What are the implications of the drug binding
to the host protein?
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Efficacious target
Secondary pharmacology
Metabolism of drug
Convert pro-drug to active form
The Project
• We are looking to Collaborate: 4+ Pharma, 3+ Vendors,
2+ Academic/Database providers
• Define a small ontology of “types” of drug target
• Create an implementation-independent standard to
represent target-types in vendor systems
• Analyse how vendor content would fit this standard
• If possible, assist vendors in adopting this standard
• Discuss standard with non-commercial providers/public
domain ontologies
• Est Cost: low $$, intellectual input required
Pharma Could Aid Vendor Adoption
• We have already mapped many non-single protein
targets to types within our systems
• We could contribute these back to vendors in the form
of:
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<TARGET> <TYPE>
• Vendors could then load these back into their systems
without any limitation
• Vendors would then only need to add target typing going
forward
• Cross-pharma means good consensus view of target-2-form
mappings
Output
• Would be a simple
table of types, typeids and definitions
• Vendors then able to add target –type
mappings in their systems
ID
Name
Def
DTS1
Single Protein
Target
A target which is
a single protein
DTS2
Fuzzy protein
target
A known protein
target where the
list of proteins is
ambiguous
DTS3
Complex
A protein
complex drug
target
• Targets would also list public
database protein identifiers.
• The combination of the two helps
consumers understand the nature and
composition of non-single protein
targets
• Recommendations on other meta-data
essentials (e.g. organism, mutation
etc) would also be defined
– PDE5 = DTS1
– Protein Kinase C = DTS2
– Gastric Pump = DTS3
Application of Target Form Ontology
Fuzzy
Fuzzy groups
Fuzzy families
Non-protein targets
Target
form
ontology
Granular
Single protein
Well-defined
complex
GO CC
GO:0005694 Large Ribosomal Subunit
has_target_form complex shared by grampositive bacteria
GO MF
GO:0004697 Protein Kinase C activity
has_target_form fuzzy group with shared
activity
PRO
complex
PRO
PRO:xxx integrin alpha4 beta1
has_target_form well-defined complex
PRO:000000535 has_target_form single protein
Vendor implementation
• The types would be a purely abstract list, there
would be no requirement for vendors to change
their database infrastructure
• Only change that would be required is the
addition of the “type” identifier within their
system (e.g. new db column, new field etc)
• We will not dictate how the information should
be presented, only that the field should be
available within the data
Benefits
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Questions this will address (Core)
– What type of target is this?
– What are the molecular
components of this target?
– How are the molecular
components of this target
related?
– How does this target relate to
other targets?
– How can information in two
separate sources be associated
to the same target concept?
Questions this will address (Fact
Identification Module)
– What are all the synonyms for
this target?
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Industry:
Deal with a specific, common problem
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Namely the representation and
integration of drug target associated data
across public and commercial sources
Develop a more complete picture of the
existing drug target universe
Explore business models that include
fully public and licencing elements
Contribute to the PRO ontology?
Content Providers
Reduction in the cost of development
and the cost of sale of drug-target data
products
Customer ready solution
Increased potential to find target
specific data is increased, maximising
use of content
Address incomplete and inconsistent
search results and customer satisfaction
Moving Beyond
• This is a small project, to address a specific issue.
• However, this should also create a base upon which to
build. The group may explore:
– Further development of Target instance and family ontologies
– Further standards around
competitor/chemogenomic//pharmacological data provision
– Collaborative opportunities with public domain resources
– Technology opportunities for providers & consumers in the
target space
Discussions with PRO
• PRO is the public domain, OBO-compliant protein
ontology http://pir.georgetown.edu/pro/pro.shtml
• We have opened a dialog to understand what aspects of
target standards could be represented by PRO. Would
start to address the “public URI” problem
• There is an option of a cross-industry funded researcher
placed in an academic group to implement standards in
a resource such as PRO
• Early days. Does not preclude the involvement of other
groups or other mechanisms
Acknowledgements
• Pistoia Member Companies & Individuals
• Pistoia Vocabulary Standards Group
• OBO Co-ordinators
Vocabulary Standards Initiative Pilot:
Molecular Drug Target Reporting Standard
Project Objectives
Activities / Deliverables
• To identify a methodology to represent drug targets
within information systems which is simple and can be
implemented at minimal cost to the provider
• Specifically:
• To create a rule-base for the description of complex
molecular drug targets
• To create a controlled vocabulary for representing
drug target classes
• To consider additional “add-on” components (e.g.
synonyms & text-search capabilities) which would
add considerable value to all participants
• To deliver a specification document which can be used
in a next phase of a Pistoia, IMI or other funded
programme to deliver a suitable implementation
• Development of a project team of
interested parties
• Agree area of focus for pilot
• All parties agreed of major outcome is
specification document
• All parties agree components of the
specification
• All parties prepared to submit exemplar
data for the specification
• All parties to review existing standards and
make recommendations on their use within
this initiative
• Provider and industry review value, cost,
technical feasibility and minimum core
services required to move to specification
• OBO guidance on utility as an “ontology”
and value within the public domain
• Primary delivery of the pilot is a
specification report, documenting
requirements & recommendations for any
subsequent implementation.
Business Challenge
• No universal standard for describing a molecular
drug target within structured content:
• For Consumers:
• Inability to navigate, find and exploit
information on a core pharmaceutical entity.
Inability to use same standard to connect
internal & external data
• For providers:
• Undermines efforts to make data more
accessible. Missing results, reducevalue of
product
Background
• For community:
• No knowledge of industry/provider experience
dealing with these concepts to increase
definition and access
for all.
Background
• Pistoia Alliance sponsored project.
• Part of the Vocabulary Standards Initiative (VSI)
within the KIS Domain.
Success Criteria
• 4+ pharma, 4+ supply chain company participants
at least one academic group
• Agreed specification document generated by end
2010. Including 2+ content provider assements of
feasability of deployment. Agreed pharma
commitment to implementation via IMI
• Clear picture of feasibility from all stakeholders
and >75% of partners interested in longer term
service.
Stakeholders & Resource Requirements
• Pistoia Alliance
• Chair: Pfizer, GSK
• Relatively low level funding, time/input from members
will be critical
• Will open dialog with the PRO group (and other
interested parties) as to support in the public domain
Key Milestones
Dec 09
Jan 10
VSI Kick-off
M
Pilot Planning
Feb 10
Q2 10
Mar 10
Pilot Planning &
Recruitment
M
Q3 10
Q4 10
Target Ontology Kick-off
Resourcing
& IP
• Inability to separate requirements from
implementation
• Inability to identify common path to
adoption
• IMI Pharmacological space call, opportunity
for funding but also complex logistics
• “PRO” protein ontology, opportunity to
enhance this resource in tandem
Expected Benefits (Value)
EBI OBO Meeting
M
Threats / Opportunities
Execution
Q1 11
• Reduce system development costs
(supplier)
• Reduced integration costs (consumer)
• Improved usability of Drug target
information
• Improved scientific analysis and hypothesis
generation capabilities for all
• Increased
visibility
content.
Draft.
V1.2of19-01-2010