Knowledgebase Creation & Systems Biology: A new prospect in discovery informatics

1. Knowledgebase Creation & Systems Biology: A new prospect in discovery informatics S.Shriram, Siri Technologies (Cytogenomics), Bangalore

2. What is a knowledgebase? 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

3. 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

4. Advantages of Knowledgebase • 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

5. 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

6. Path to Knowledgebase Database Infobase Knowledgebase

7. Creation of Knowledgebase • 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)

8. 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.

9. Drug Discovery –Emerging needs for Knowledgebase Bioinformatics Chemo-informatics Drug Target identification Target evaluation and selection Lead identification/optimization Process development Preclinical evaluation Clinical evaluation Curated Knowledgebase

10. Types of Knowledgebase Pathways Gene/Protein/Target Ligands/ Drugs

11. Integrated Platform for Bio and Chemo Knowledgebase Patent & Published Literature Proprietary Data Bioinformatics Chemoinformatics Integrated Knowledgebase

12. Patents & literature Structure 2D, 3D Physico-chemical properties Synthesis Drug Targets Ligand Centric Target Sequence Analogs Target Structure (3D) SAR Ligand – target interaction Assay / Bioactivity ADME and Toxicity Regulatory information Ligand centric knowledgebase Combinatorial chemistry Pharmacophore models

14. OMIM UniGene Probeset Homologene BODYMAP LocusLink GenBank SWISS-PROT Homologous Data Integration Integrated Database

15. 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

16. Caspase Pathway

17. Features 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

23. Building blocks of SYSTEM BIOLOGY Organism / disease Cell / tissue Pathways Gene/Protein/Target Ligands/ Drugs

24. Why we need biological systems? • To figure out • What is the effect of an intervention in one part of the system, and its associated problem? • What intervention one has to make in order to obtain some desired result? • Key Players • Physiome Sciences • Entelos Inc.

25. Clinical Response Molecular Target Gene Chips Fragmented Expertise Integrated Knowledge High-Throughput Systems Healthcare Alliances Knock-outs Predictive biology Computer Simulation Predictive Biological Models Novel Insights Bioinformatics

27. Example Since these equations are completely defined by the knowledge of connectivity of a network, and knowledge of various transition rate constants, and since these quantities are all stored in a databases, the equations may be generated automatically on a computer

31. Bill Allen resident cell activation inflammatory cell influx resident cell activation inflammatory cell influx 8% improvement in FEV1 21% improvement in FEV1

32. Applications of Systems Biology • Understanding disease dynamics • Test hypotheses of a disease pathology • Ask better questions • Plan better experiments • Identify and fill the knowledge gaps • Bridging biochemistry to clinical outcomes • Target assessment & prioritization • Drug candidate advancement • Combination therapy assessment • Designing and understanding clinical studies • Patient selection and dosing • Surrogate marker prediction

33. Entelos demo

34. Thanks to • Siri Technologies • Cytogenomics • Jubilant Biosys • Entelos • Physiome Sciences

35. Thank you