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

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?

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

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

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

Path to KnowledgebasePath to KnowledgebasePath to KnowledgebasePath to Knowledgebase

Knowledgebase

Database

Infobase

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

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.

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

Types of KnowledgebaseTypes of KnowledgebaseTypes of KnowledgebaseTypes of Knowledgebase

Ligands/Drugs

Gene/Protein/Target

Pathways

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

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

Data IntegrationData IntegrationData IntegrationData Integration

Integrated DatabaseIntegrated Database

HomologeneHomologene

LocusLinkLocusLink

SWISS-PROTSWISS-PROT

HomologousHomologous

GenBankGenBank

BODYMAPBODYMAP

ProbesetProbeset

UniGeneUniGeneOMIMOMIM

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

Caspase Pathway

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

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

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.

Predictive biologyPredictive biologyPredictive biologyPredictive biology

GeneGeneChipsChips

High-ThroughputHigh-ThroughputSystemsSystems

Knock-outsKnock-outsHealthcareHealthcareAlliancesAlliances

Bioinformatics

PredictiveBiologicalModels

FragmentedFragmentedExpertiseExpertise

IntegratedIntegratedKnowledgeKnowledge

ComputerSimulatio

n

NovelInsight

s

ClinicalClinicalResponseResponse

MolecularMolecularTargetTarget

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

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

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

Entelos demo

Thanks toThanks to

Siri Technologies Cytogenomics Jubilant Biosys Entelos Physiome Sciences

Thank youThank youThank youThank you