bioinformatics to chemistry to therapyacscinf.org/docs/meetings/234nm/presentations/234nm73.pdf ·...

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T H O M S O N S C I E N T I F I C

Donald WalterAugust 22, 2007

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

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Copyright 2007 Thomson Corporation 2


The Typical Drug Development Paradigm

Gary Thomas, Medicinal Chemistry: An Introduction, John Wiley & Sons, Chichester, 2000

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A sample case; Treatment of hypertension by losarta n

• 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)

http://www.mayoclinic.com/health/angiotensin-II-receptor-blockers/HI00054

Also see Wong, Pancras C.; Timmermans, Pieter B. M. W. M. 1996. Historical development of Losartan (DuP 753) and angiotensin II receptor subtypes. Blood Pressure 5 (SUPPL. 3): 11-14.



Find targets relating to angiotensin II

• In Thomson Pharma; the easiest search

• The more powerful search

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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



The target report

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The target report (contd)




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Sequence report



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Two new bioinformatics resources – BINDplus and BONDplusBINDplus - 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 peer-reviewed 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, identifier, or BLAST search

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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.



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.

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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)

BINDplus: Types of Records



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

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BIND Accession ID

Interacting molecules with descriptions

External links to NCBI and other databases

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.

Domain information & Gene Ontology (GO) annotation

Publication information supporting the interaction

BINDplus: Detailed Record



Experimental details:E.g. experimental system,relevant mutations and experimental forms

Associated binding sites

Experimental evidence can be visually linked to relevant binding sites

BINDplus records contain comprehensive details on published experimental data supporting the interaction.

Detailed binding site information

BINDplus: Detailed Record (cont’d)

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BONDplus

• BOND (B iomolecular 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.



BONDplus Model

HighValue

FoundationalInformation

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BONDplus Content: Sequence Data



BONDplus: Search Results

Complex Query Builder

Exclude untrusted results

Retrieve both Sequence andInteraction results

Summary Sequence Information

Multiple View/Export Formats

bioinformatics to chemistry to therapyacscinf.org/docs/meetings/234nm/presentations/234nm73.pdf ·...

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