Bioinformatics to chemistry to therapy: Some case studies deriving information from the literature

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1 Bioinformatics to chemistry to therapy: Some case studies deriving information from the literature. Donald Walter August 22, 2007 The Typical Drug Development Paradigm Gary Thomas, Medicinal Chemistry: An Introduction, John Wiley & Sons, Chichester,

2 A sample case; Treatment of hypertension by losartan High blood pressure can be caused by narrowing of the blood vessels. It can lead to heart disease, strokes and kidney failure Angiotensin II is a natural substance in your body that affects your cardiovascular system in many ways, such as by narrowing your blood vessels. This narrowing can increase your blood pressure and force your heart to work harder. Angiotensin II also stimulates the release of aldosterone, a hormone that increases your body's retention of sodium and water, which can lead to increased blood pressure. It can also thicken and stiffen the walls of your blood vessels and heart Angiotensin II receptor blockers block the action of angiotensin II. That allows blood vessels to widen (dilate) Losartan (COZAAR or HYZAAR) is a selective angiotensin II AT-I receptor antagonist (HYZAAR is Losartan+HCT) Also see Wong, Pancras C.; Timmermans, Pieter B. M. W. M Historical development of Losartan (DuP 753) and angiotensin II receptor subtypes. Blood Pressure 5 (SUPPL. 3): Find targets relating to angiotensin II In Thomson Pharma; the easiest search The more powerful search 4 2

3 Find sequences relating to angiotensin II Results; 3 target reports. Angiotensin II AT-1 receptor TG Angiotensin II AT-2 receptor TG Angiotensin II receptor Let s look at the first one 5 The target report 6 3

4 The target report (contd) 7 The target report (contd) 8 4

5 The target report (contd) 9 The target report (contd) 10 5

6 Sequence report

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8 15 Two new bioinformatics resources BINDplus and BONDplus BINDplus - human-curated, biomolecular interaction data BINDplus represents the global standard for biomolecular interaction data BIND IDs published in Nature, Science and Cell BINDplus contains interaction information extracted from text and figures, and compiled in a standardized and computable form The BINDplus editorial team aims to capture all interaction data from over 120 peerreviewed publications BONDplus Sequence, interaction, taxonomy, publication, annotation, domain, cross-reference data on a Web platform Public Data - Over 80 million public domain sequences, originating GenBank, RefSeq, Entrez Gene, and UniProt/SWISSPROT GENESEQ Integrated on BONDplus BINDplus Largest, most comprehensive interaction database available Growing database of 200,000 interactions All databases fully searchable via free text, 16identifier, or BLAST searchcopyright 2007 Thomson Corporation 8

9 BINDplus BINDplus - human-curated, biomolecular interaction data BINDplus represents the global standard for biomolecular interaction data BIND IDs published in Nature, Science and Cell BINDplus contains interaction information extracted from text and figures, and compiled in a standardized and computable form Aims to capture all interaction data from over 120 peer-reviewed publications The Biomolecular Interaction Network Database (BIND) is a collection of over 200,000 records documenting molecular interactions: 60,000+ Gene Identifiers (GIs) 1,545+ organisms 23,800+ papers 7,500+ Gene Ontology (GO) terms New records are added to BINDplus daily With over 2,000 data fields, BINDplus includes clearly-labelled high-throughput (HTP) data submissions and low throughput (LTP) hand-curated information. To keep users at the cutting edge of global research, BINDplus is updated in real time every hour. 17 BINDplus: Contents (cont d) Physical interactions involving protein, DNA, RNA, small molecule, complex, photon from any/all organisms. Information about the interaction Experimental evidence Binding sites Chemical action/state between A and B Cellular localization Kinetic data Publication information Reflects the peer-reviewed opinion of the publication author. Interacting molecules are identified by referencing object databases. (e.g., NCBI s GenBank, OMIM, SGD, MGI, RGD, FlyBase) Focus is on details of interaction, not the interacting molecules. 18 9

10 BINDplus: Types of Records Interaction: Detailed description of an interaction between two molecules that is believed to occur in vivo. Complex: Describes a molecular complex by listing the series of interaction records present in the complex. (Eg. multi-subunit enzymes, ribosomes) 19 BINDplus: Record Creation BINDplus records are created using two methods: 1. Low Throughput Entry Hand-curated by specially-trained postgraduate-level scientists High-value data generated by standard wet-lab research 2. High Throughput Imports Automated experiments generating large scale datasets which are imported to BINDplus using individual scripting methods by developer curators Date generated from high throughput experiments such as large scale Yeast Two Hybrid 20 10

11 BINDplus: Detailed Record Detailed BINDplus records can be viewed in an expanded or collapsible format, enabling you to access as much or as little information as you need. BIND Accession ID Publication information supporting the interaction Interacting molecules with descriptions External links to NCBI and other databases Domain information & Gene Ontology (GO) annotation 21 BINDplus: Detailed Record (cont d) BINDplus records contain comprehensive details on published experimental data supporting the interaction. Experimental details: E.g. experimental system, relevant mutations and experimental forms Associated binding sites Experimental evidence can be visually linked to relevant binding sites Detailed binding site information 22 11

12 BONDplus BOND (Biomolecular Object Network Databank) integrates a range of component databases including Genbank and BIND Contains 80+ million biological sequences, 33,000 protein structures, 38,000 GO terms, and over 200,000 human curated interactions contained in BIND. 23 BONDplus Model High Value Foundational Information 24 12

13 BONDplus Content: Sequence Data 25 BONDplus: Search Results Complex Query Builder Exclude untrusted results Retrieve both Sequence and Interaction results Multiple View/Export Formats Summary Sequence Information 26 13