Guide to PHARMACOLOGY: a web-Based Compendium for Research and Education

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www.guidetopharmacology.org

The IUPHAR/BPS Guide to PHARMACOLOGY (GtoPdb): A Web-Based Compendium for

Research and Education

Dr. Christopher Southan (on behalf of the GtoPdb team) presented at Skaggs School of Pharmacy, UC San Diego, hosted by Prof. Michael Gilson, March 2016

http://www.guidetopharmacology.org

http://www.slideshare.net/cdsouthan/guide-to-pharmacology-a-webbased-compendium-for-research-and-education

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Abstract

This database (GtoPdb) is a leading on-line resource of key relationships in molecular pharmacology, encompassing a network of ~8000 ligands X ~1500 human proteins they quantitatively interact with (PMID 26464438). It has been used by researchers and educators worldwide since its first incarnation as IUPHAR-DB in 2009. This presentation will address who might use this resource and how . Ways to navigate pharmacological relationships and drug mechanisms of action will be shown for the web interface, target hierarchy and cross-references to other resources. In addition our new educational site will be introduced as well as the latest set of “Concise Guide” overview papers (PMIDs 26650438-46) derived directly from the database content.

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DATABASE CONTENT

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GtoPdb content - targets>2700 established or potential drug targets and related proteins:

• G protein-coupled receptors (Class A, B, C, frizzled, adhesion and orphan GPCRs)

• Ligand-gated ion channels• Voltage-gated ion channels• Other ion channels• Nuclear hormone receptors• Catalytic receptors• Kinases• Proteases• Other enzymes• Transporters• Other protein targets

Target numbers as of December 2014

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>8000 ligands and drugs:• Approved drugs• Synthetic organic compounds• Metabolites, hormones, neurotransmitters• Natural products• Endogenous peptides• Other peptides• Inorganics• Antibodies• Labelled ligands

GtoPdb content - ligands

Ligand numbers as of December 2014

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Concise target family summaries• Concise target family summaries introducing the main

properties • Expert overviews and comments• Selective ligands, clinicically-used drugs, endogenous

ligands and probes (radioligands and PET ligands where available)

• Further reading lists

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Detailed annotation for selected targets

Data are collected and reviewed by NC-IUPHAR subcommittees and individual experts:

• Gene and protein information• IUPHAR nomenclature and synonyms • Extensive pharmacology: agonist, antagonist and allosteric

regulator affinities, ion channel blockers, enzyme/transporter inhibitors and substrates

• Signal transduction mechanisms; Tissue distribution• Functional assays; Physiological functions• Mouse gene knockout phenotypes• Clinically-relevant mutations and pathophysiology• Gene expression changes in disease; Biologically significant

variants

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Other features• Extensively referenced and linked to primary literature in

PubMed• Focus is on human data but where species differences

exist or literature data unavailable other species are given• Linked to corresponding entries in other resources, e.g.

UniProt, Ensembl, Entrez Gene, KEGG, OMIM, ChEMBL• Ligand information including structure, peptide

sequences, clinical data and nomenclature, linked up to chemistry resources including PubChem

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NAVIGATING THE WEBSITE AND SEARCH TOOLS

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Navigating GtoPdb

• Browse lists of targets and ligands• Target families are listed under expandable family trees• Target information is presented in two levels of detail

1. Concise family summary pages2. Detailed pages for selected targets

• Ligand pages are provided for all compounds in GtoPdb• Use the search tools to search by name, keyword,

identifier or ligand structure

Home Page

GtoPdb home page

Histamine receptors family summary page

Histamine H2 receptor concise summary view

Reference information and linkout to PubMed

Link to more details for the H2 receptor

H2 receptor detailed annotation page

Linkouts to other gene and protein resources

Click for species-specific selectivity table

Ligand is endogenous in this species

Ligand is labelled

Ligand is radioactive

Approved drug

Primary target of this compound

Interaction tables

Ligand page for the approved drug ranitidine

Biological activity data for ranitidine at targets in the database

Clinical use and mechanism of action for ranitidine

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Peptide ligand information

• Curated sequence information

• Post-translational and chemical group modifications

• Precursor proteins and encoding genes

• Similar sequences

Ligand page for the endogenous peptide endothelin-1

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Bespoke tables for different targets• Heteromeric complexes: subunit composition• GPCRs: signal transduction mechanism• Ion channels: ion conductance and voltage-dependence• Nuclear receptors: DNA co-binding partners, target genes• Enzymes: substrates, cofactors, reaction mechanisms• Transporters: substrates

GABAB receptorisopentenyl-diphosphate Δ-isomerase 1

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Database search functionality• Quick search box at the top of every page with

autocomplete for target, family and ligand names

• Advanced searches are available on the Target Search and Ligand Search pages

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Target search tools• Search by name or keyword, identifier (e.g. UniProtKB

accession) or reference (e.g. PubMed id)

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Ligand search tools• Search by name, identifier (e.g. PubChem CID, InChI) or

structure (exact match, similarity, substructure, SMARTS)

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Advanced search by keyword• Keyword searches, for example by disease name, can

facilitate retrieval of associated ligands and targets

A search for “Alzheimer’s disease” returns implicated targets and ligands tested in clinical trials

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Spread of approved drug numbers

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Comparing UniProt curated druggable protein sources

Proteins all: 31788 6162 1957 1833

Select example: “database:(type:guidetopharmacology) AND reviewed:yes AND organism:"Homo sapiens (Human) [9606]“ = 1379

PubChem CIDs: 540313 1458720 7426 6293

Swiss-Prot hum: 2245 2935 1640 1379

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Human Swiss-Prot intersects and differentials

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CONSISE GUIDE AND THE EDUCATION SITE

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Fruits of our labour

IUPHAR/ASPET Pharmacology Education Project PEPhttp://www-test.drupal.is.ed.ac.uk/www-test.pep.ed.ac.uk/

Information is being supplied by members of the Editorial Board, or created in-house by the curator. Premise is to provide a synopsis for each topic, plus links to good quality on-line learning resources.

Pharmacology sectionhttp://www-test.drupal.is.ed.ac.uk/www-test.pep.ed.ac.uk/pharmacology

Drugs-cardiovascular systemhttp://www-test.drupal.is.ed.ac.uk/www-test.pep.ed.ac.uk/drugs/cardiovascular-system

Topics

Pharmacology-Ion Channelshttp://www-test.drupal.is.ed.ac.uk/www-test.pep.ed.ac.uk/pharmacology/ion-channels

Pharmacology- pharmacodynamicshttp://www-test.drupal.is.ed.ac.uk/www-test.pep.ed.ac.uk/pharmacology/pharmacodynamics

Clinical Pharmacology-drug development & marketinghttp://www-test.drupal.is.ed.ac.uk/www-test.pep.ed.ac.uk/clinical-pharmacology/drug-development-and-marketing

Topics

Drugs-cardiovascular systemhttp://www-test.drupal.is.ed.ac.uk/www-test.pep.ed.ac.uk/drugs/cardiovascular-system

Topics

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END NOTES

Acknowledgements• The late Prof Tony Harmar, founder and original PI• Michael Spedding, Steve Alexander, Ian McGrath, Anthony Davenport, John

Peters and all past and present members of NC-IUPHAR• NC-IUPHAR subcommittees and Concise Guide to PHARMACOLOGY

contributors• Database team:

• Jamie Davies (Principal Investigator)• Joanna Sharman (Developer)• Adam Pawson, Helen Benson, Elena Faccenda and Christopher Southan (Curators)• Veronika Divincova (Project Administrator)

• Database team alumni• IUPHAR/BPS Guide to PHARMACOLOGY funders:

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Stay in touch• NC-IUPHAR and GtoPdb team newsletter• Receive email alerts for new content and news items• Follow us on• Download slides and posters• Email us with any questions, comments,

[email protected]

@GuidetoPHARM