Knowledgebase Creation & Systems Biology: A new prospect in discovery informatics
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Transcript of Knowledgebase Creation & Systems Biology: A new prospect in discovery informatics
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Knowledgebase Creation & Systems Biology:
A new prospect in discovery informatics
Knowledgebase Creation & Systems Biology:
A new prospect in discovery informatics
S.Shriram,Siri Technologies (Cytogenomics),
Bangalore
S.Shriram,Siri Technologies (Cytogenomics),
Bangalore
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A knowledgebase provides an integrated approach to biological simulation that combines process, technology, tools and applications for solving complex problems and for data representation, validation and prediction
What is a knowledgebase?What is a knowledgebase?What is a knowledgebase?What is a knowledgebase?
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The use of simulation in pharmaceutical research enables investigators to anticipate potential issues in the drug discovery process and to select the best overall design principles in advance of real-life studies
Knowledgebases forms the base for SYSTEM BIOLOGY - ie study of biological systems using a holistic approach
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Access proprietary and public databases, data analysis tools, and computer algorithms within a single, expandable, web-based software environment
Streamline data analysis and interpretation Share experimental data and models across
organizational networks
Advantages of KnowledgebaseAdvantages of KnowledgebaseAdvantages of KnowledgebaseAdvantages of Knowledgebase
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Advantages….Advantages….
Explore new experimental scenarios, test hypotheses, and generate predictive information
Create, run, modify and routinely upgrade detailed models of cells, tissues and organs with little or no dependence on highly trained programmers
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Path to KnowledgebasePath to KnowledgebasePath to KnowledgebasePath to Knowledgebase
Knowledgebase
Database
Infobase
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Identify the disease and tissue (eg. pancreatic cancer and pancreas and other related tissues)
Data to be gathered form curation of literature, experiments(eg. gene expression studies), clinical studies and analysis/interpretation of these details to extract information (eg. identify targets/side effects of known drugs in the pathways)
Creation Creation of of KnowledgebaseKnowledgebaseCreation Creation of of KnowledgebaseKnowledgebase
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Creation…Creation…
Represent complex experimental data in mathematical form and then uses these equations to build customized biological models
Models to aid prediction of effects of new drugs, etc.
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Drug Discovery –Emerging needs for Drug Discovery –Emerging needs for KnowledgebaseKnowledgebase
Drug Discovery –Emerging needs for Drug Discovery –Emerging needs for KnowledgebaseKnowledgebase
Chemo-informatics
Curated Knowledgebase
Target identification
Target evaluation and
selection
Lead identification/o
ptimization
Process development
Preclinical evaluation Clinical
evaluation
Bioinformatics
Drug
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Types of KnowledgebaseTypes of KnowledgebaseTypes of KnowledgebaseTypes of Knowledgebase
Ligands/Drugs
Gene/Protein/Target
Pathways
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Integrated Platform for Bio and Integrated Platform for Bio and Chemo KnowledgebaseChemo Knowledgebase
Integrated Platform for Bio and Integrated Platform for Bio and Chemo KnowledgebaseChemo Knowledgebase
Patent & PublishedLiterature
Proprietary Data
Bioinformatics Chemoinformatics
Integrated Knowledgebase
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Ligand centric knowledgebaseLigand centric knowledgebaseLigand centric knowledgebaseLigand centric knowledgebase
Pharmacophore models
Combinatorial chemistry
LigandCentric
Structure 2D, 3D
Drug Targets
Target Sequence
Target Structure (3D)
Patents & literature
Synthesis
Assay / Bioactivity
SAR
Physico-chemical properties
Ligand – target interaction
Regulatory informationADME and Toxicity
Analogs
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Data IntegrationData IntegrationData IntegrationData Integration
Integrated DatabaseIntegrated Database
HomologeneHomologene
LocusLinkLocusLink
SWISS-PROTSWISS-PROT
HomologousHomologous
GenBankGenBank
BODYMAPBODYMAP
ProbesetProbeset
UniGeneUniGeneOMIMOMIM
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Features of pathway database
• Clickable maps that give data on the proteins of interest
• Multiple search modes, including protein, signaling
molecule and ligand structure based searches and other
filters like physiology, organism, disease state etc
• Provision for a comprehensive account of the diseases,
to enable the user to build and visualize non-canonical
pathways
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Caspase Pathway
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Features of Pathway KnowledgebaseFeatures of Pathway KnowledgebaseFeatures of Pathway KnowledgebaseFeatures of Pathway Knowledgebase
Tagging of gene expression data (from Microarray, SAGE, etc) onto the simple clickable pathway maps.
In-silico manipulation of pathways – ie predict the alterations in expression levels in any given tissue or disease conditions
Ease target prioritization
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Building blocks of SYSTEM BIOLOGYBuilding blocks of SYSTEM BIOLOGYBuilding blocks of SYSTEM BIOLOGYBuilding blocks of SYSTEM BIOLOGY
Ligands/Drugs
Gene/Protein/Target
Pathways
Organism / disease
Cell / tissue
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Why we need biological systems?Why we need biological systems? Why we need biological systems?Why we need biological systems?
To figure out To figure out WWhat is the effect of an intervention in one hat is the effect of an intervention in one
part of the system, and its associated part of the system, and its associated problem? problem?
WWhat intervention one has to make in order to hat intervention one has to make in order to obtain some desired result?obtain some desired result?
Key PlayersKey Players
Physiome SciencesPhysiome Sciences
Entelos Inc.Entelos Inc.
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Predictive biologyPredictive biologyPredictive biologyPredictive biology
GeneGeneChipsChips
High-ThroughputHigh-ThroughputSystemsSystems
Knock-outsKnock-outsHealthcareHealthcareAlliancesAlliances
Bioinformatics
PredictiveBiologicalModels
FragmentedFragmentedExpertiseExpertise
IntegratedIntegratedKnowledgeKnowledge
ComputerSimulatio
n
NovelInsight
s
ClinicalClinicalResponseResponse
MolecularMolecularTargetTarget
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ExampleExampleExampleExample
Since these equations Since these equations are completely defined are completely defined by the knowledge of by the knowledge of connectivity of a network, connectivity of a network, and knowledge of and knowledge of various transition rate various transition rate constants, and since constants, and since these quantities are all these quantities are all stored in a databases, stored in a databases, the equations may be the equations may be generated automatically generated automatically
on a computeron a computer
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AllenAllen
resident cell resident cell activationactivation
inflammatory inflammatory cell influxcell influx
BillBill
resident cell resident cell activationactivation
inflammatory inflammatory cell influxcell influx
8% improvement in FEV1 21% improvement in FEV1
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Applications of Systems BiologyApplications of Systems BiologyApplications of Systems BiologyApplications of Systems Biology Understanding disease dynamicsUnderstanding disease dynamics
• Test hypotheses of a disease pathologyTest hypotheses of a disease pathology
– Ask better questionsAsk better questions
– Plan better experimentsPlan better experiments
• Identify and fill the knowledge gapsIdentify and fill the knowledge gaps
Bridging biochemistry to clinical outcomesBridging biochemistry to clinical outcomes
• Target assessment & prioritizationTarget assessment & prioritization
• Drug candidate advancementDrug candidate advancement
• Combination therapy assessment Combination therapy assessment
Designing and understanding clinical studiesDesigning and understanding clinical studies
• Patient selection and dosingPatient selection and dosing
• Surrogate marker predictionSurrogate marker prediction
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Entelos demo
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Thanks toThanks to
Siri Technologies Cytogenomics Jubilant Biosys Entelos Physiome Sciences
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Thank youThank youThank youThank you