IUPHAR DATABASE

Contents

About IUPHAR-DB
Search Facility
Database Tables
GPCR Tables
Ion Channel Tables
Nuclear Receptor Tables
Ligand Pages

About IUPHAR-DB

IUPHAR-DB contributors
The IUPHAR database is developed under the auspices of NC-IUPHAR to provide an accurate educative resource to the scientific community. It relies on contributions by expert pharmacologists who volunteer their time. All contributors are attributed on the website, allowing receptor data pages to be properly cited.

Annotation procedure
NC-IUPHAR has a network of expert subcommittees (presently over 60), each responsible for developing the nomenclature for a receptor family and contributing data. Where no relevant subcommittee exists, data are captured by the curators or individual experts and peer reviewed by at least two external expert referees.

The data
The data are summarised from selected primary literature articles, which are linked to PubMed. Where possible the data are linked to other relevant databases for further information.

If you would like to get involved in reviewing, contributing to the data tables or just to make any comments please contact the curators: curators@iuphar-db.org.

Colour codes
Each family and receptor are given a colour code to indicate the status of their annotation in IUPHAR-DB:

Annotated and expert reviewed: Data have been annotated and reviewed by an expert. Please contact us if you can help with updates.
Annotated and awaiting review: Available data have been entered by experts or curators but are yet to be reviewed by independent experts. Please contact us if you can help with reviewing.
Awaiting annotation/under development: These pages are awaiting annotation. A minimum amount of data are displayed about receptors, e.g. nomenclature and database links. Whilst some pages are under development, others still need volunteers so please contact us if you can help with annotation.

Search Facility

A quick text search box is provided in the left sidebar of all pages. Just enter keywords in the text field and press 'Search the database' to perform a matching text search on all data fields.

Advanced search tools can be accessed by following the links below the quick text search box on the left. Advanced search tools allow text searches on specific database fields, as well as non-text searches e.g. by accession number or chemical structure. Depending on the type of data you wish to search for you can choose between receptor search tools and chemical search tools.

Receptor search tools

Receptor text search: perform keyword searches of selected database fields.
1. Type the search term(s) into the text box.
2. If multiple words are entered they must all be present for a result to be returned.
3. Select the field(s) from the list that you wish to search.
4. To select multiple fields hold down CTRL while selecting the fields.
5. To search the entire database select 'All' at the top of the field list.
6. You can optionally choose to limit your results by species and receptor type.
Search by database identifier: retrieve receptors by entering an external database identifier or a gene name, e.g. Entrez gene id or HGNC approved name.
1. Type the identifier into the text box.
2. Select the source database from the drop-down list.
3. Multiple identifiers can be searched by separating them with spaces. If they are from different source databases, select 'Unknown' in the database list.
Search for literature references: search for families where a particular literature reference appears.
1. Type a keyword, article title, author last-name or PubMed Id into the text box.
2. Select the type of query to perform from the drop-down list.
3. Multiple PubMed identifiers may be entered separated with spaces.

Ligand search tools

Ligand name search: retrieve compounds by matching to their name. Also (optionally) searches in receptor interaction comment fields (agonists, antagonists etc) for matches.
1. Type the search term(s) into the text box.
2. If multiple words are entered they must all be present for a result to be returned.
3. Check the box to include searches on comment fields or uncheck to exclude.
Search by database identifier: retrieve compounds by entering an external database identifier, e.g. PubChem CID or ChEBI id (in this case the number must be prefixed with "CHEBI:").
1. Type the identifier into the text box.
2. Select the source database from the drop-down list.
3. Multiple identifiers can be searched by separating them with spaces. If they are from different source databases, select 'Unknown' in the database list.
Chemical structure search: search for compounds by chemical structure. Performs substructure, SMARTS, similarity and identity (exact) searches.

Substructure

This search uses the Dotmatics Pinpoint algorithm to match a drawn 2D/Markush structure and returns any compounds which contain the query structure.

SMARTS

Uses Pinpoint for matching Daylight SMARTS and returns any compounds which match the query.

Similarity

Similarity search uses the Tanimoto coefficient to compare the similarity between the query molecule and molecules in the database using Pinpoint generated expanded fingerprints and returning all molecules above a user selected threshold (>70% or 85%).
Please note: if your similarity search does not return appropriate results please try using the substructure function. (We are currently working on optimising our similarity search.)

Exact

Exact match query returns all compounds matching the canonical SMILES, with no regards to the chiral specification. This is attained by Tanimoto comparison of fingerprints and returning all with 100% similarity.
1. Either: enter a SMILES or SMARTS representation of the chemical structure into the text box and press 'Import SMILES/SMARTS' to load the structure into the editor.
2. Or: draw the chemical structure into the editor. The icon in the top right above the atoms can be used to add other atoms, R groups and SMARTS groups.
3. Choose the type of search to perform from the drop-down menu on the top right (e.g. similarity - high).
4. Choose the type of chemical class to search for (recommended type is small molecules but peptides and others are available).
5. Currently the search function does not consider chiral specification of matched compounds. This is to ensure that all relevant results will be returned. Please ensure that your input structure does not include chiral specification, otherwise substructure and SMARTS searches may miss relevant structures.
6. The returned structures are roughly ordered according to their flexibility/complexity.
7. On the results page, clicking on a ligand's image or name will take you to its ligand page. Clicking on the 'Use in search' button will load the ligand into the editor so it can be modified if required and used in a further search.

Database Tables (All Receptors)

Click here for an interactive PDF image of a receptor page (hover over red boxes to view descriptions).

Receptor - The NC-IUPHAR recommended nomenclature for a structurally and operationally distinct receptor in a given family.

Previous and Unofficial Names - Alternative names that exist in the literature, but are no longer the recommended nomenclature.

Structural Information - For human, mouse and rat receptors the following data are displayed:

Column	Definition
Transmembrane domains (TM)	The number of times the receptor polypeptide passes through the cell membrane.
Amino acids (AA)	The number of amino acids which make up the receptor protein
Chromosomal location	The genetic location of the receptor.
Gene Name	The name of the gene that codes for the receptor which, if highlighted in blue, links to the HGNC, MGI or RGD database.
P loops	(Some ion channels only) The number of pore loops in the protein

Database Links - Links are provided to other relevant resources, including several genomic databases (e.g. Ensembl, Entrez Gene, GeneCards), protein databases (e.g. RefSeq, Uniprot) and others such as ChEMBL (MedChem literature data on drug-like molecules and their targets) and PharmGKB (pharmacogenomics data).

Selected 3D Structures - Highest resolution structures were selected and an attempt was made to include for each receptor the unliganded, agonist, and antagonist bound structures where available. Links are provided to associate IUPHAR ligands with RCSB PDB ligand pages where possible.

Ligands - Ligands are arranged in tables according to their action at the receptor.
The column headings or icons in the ligand table are described below:

Icon/Table heading	Definition
	Indicates that the ligand is radioactive.
	Indicates that the ligand is endogenous in the species of the receptor under test.
	Indicates that the ligand also binds to other receptors in the database. Clicking on this icon displays these receptors as well as the ligand's potency at each receptor.
	Indicates that a 2D structure is available for the ligand and links to a ligand page where the structure can be viewed.
Hs, Mm, Rn	Indicates the species of the receptor and NOT the species of the ligand. '?' indicates that the species was not given in the original publication. Selectivity tables are not shown when the species is unknown.
Ligand	The name of the ligand, which can be clicked on to open a ligand page. Ligand pages include database links, alternative names, data on affinity for other receptors, structural information and links to similar ligands, where available.
Action	This indicates how the ligand binds to the receptor (see the terms and symbols document for a definition of the terms).
Affinity	A measure of how strongly the ligand binds to the receptor. In cases where no binding data are available functional data may be used.
Units	The units used to measure the ligand's binding to the receptor (see the terms and symbols document for a definition of the terms).
Concentration range	Where affinity data are not available, the concentration range of ligand used for the study is displayed (in M).
Holding voltage	The voltage at which the displayed affinity was determined (in mV). 'Physiological' indicates that the experiment was performed in intact cells where voltage could not be determined.

The ligands can be sorted in alphabetical order or by action, affinity, unit, concentration range or holding voltage by clicking on the column header.

Functional Assay - Details of pharmacological test systems (whole tissues or isolated cells) in which a response can be firmly attributed to the function of a defined receptor type.

Tissue Distribution - Central and peripheral distribution of the receptor (and the identifying techniques).

Physiological Functions - The physiological response mediated by the receptor if established in whole tissue, preferably in vivo.

Physiological Consequences of Altering Gene Expression - Important physiological differences observed as a result of modifying expression levels (e.g. knockouts).

Medically-Relevant Mutations - Details of the pathophysiologies in which the receptor is involved, including, where available, the ligands at the receptor which are of therapeutic use. Details are provided of individual mutations that lead to the pathophysiology, in terms of the change in the amino acid sequence.

Gene Expression and Pathophysiology - The pathophysiology that arises from abnormal gene expression.

Biologically Important Receptor Variants - Details of polymorphisms and post-transcriptional modifications (e.g. splice variation) that influence function. Where possible links to the protein and nucleotide sequences are provided.

N.B. additional species are sometimes used where data for human, rat and mouse are unavailable, the most common are: Bt (bovine), Oc (rabbit), Cp (guinea pig), Clf (dog).

GPCR Tables

Primary and Secondary Transduction Mechanisms - The preferred primary and secondary receptor signalling pathways or mechanisms, where established.

Ligands - Ligands are categorised as agonists, antagonists or allosteric regulators.

Ion Channel Tables

Voltage-gated (VGIC) and ligand-gated (LGIC) ion channels

Associated Proteins - Proteins that interact directly with the receptor either as heteromeric pore-forming subunits, auxiliary subunits or associated proteins.

Ion Selectivity and Conductance - This table displays relative or absolute conductance data for the receptor on a 'per species' basis.

Voltage Dependence - (VGICs only) This table displays the voltages of activation, inactivation and deactivation and the relevant time constants, where available.

Ligands - For LGICs, ligands are categorised as agonists, antagonists, channel blockers or allosteric regulators. For VGICs, ligands are categorised as activators, pore blockers or gating inhibitors, according to the following definitions:

Activators: Ligands that activate ion channels by binding directly to them, including ligands that cause a change in the voltage dependence of channel gating that favors activation.
Gating Inhibitors: Ligands that inhibit ion channel gating by directly binding to the channels, including ligands that inhibit ion channel activation and those that inhibit ion channel inactivation.
Pore blockers: Ligands that block ion movement through the pore of ion channels.

Nuclear Receptor Tables

Receptor name - Typically the most commonly used name for the receptor.

Nomenclature - The Nuclear Receptor Nomenclature Committee (NRNC) recommended name for the receptor. See reference:
Nuclear Receptors Nomenclature Committee (1999). A unified nomenclature system for the nuclear receptor superfamily. Cell 97, 161-163.

Ligands - Compounds that bind reversibly to NRs into the C-terminal ligand binding pocket (LBP).

Agonists: Ligands that induce an active conformation of the receptor.
Antagonists: Ligands that produce a conformation and an action of the receptor distinct from that produced by an agonist.
Inverse agonists: Ligands that can promote corepressor recruitment.
Partial agonists: Agonists that in a given tissue, under specific conditions, cannot elicit as optimal an effect (even when applied at high concentration, so that all the receptors should be occupied) as can another agonist acting through the same receptors in the same tissue.

Unliganded receptor - Considered preferable compared with apo-receptor.

DNA Binding - Hormone response elements (HRE) are DNA recognition sites which include inverted repeat DNA half sites and direct repeats (e.g. DR1-DR5) for homodimeric and heterodimeric receptors respectively.

Co-binding Partners - Proteins which specifically interact with and induce a functional effect with NRs.

Co-regulators - Macromolecules that associate with NRs to modulate their transcriptional activity; divisible into coregulators that promote positive activity (coactivators) and those that promote negative activity (corepressors).

Main Target Genes - Genes regulated directly by the actions of NRs.

Transactivation - Activation of transcription by the binding of a transcription factor (and coregulators) to a DNA regulatory sequence.

Isoforms - Products of the same gene produced by alternative splicing, alternative promoter usage, alternative translational initiation; does not consider post-translational modifications; examples: RARα1 and RARα2.

Terms and definitions were adapted from the IUPHAR Compendium.

Ligand Tables

2D Structure - An image of the ligand's 2D structure generated using the NCI/CADD Chemical Identifier Resolver. Click on the image to access a chemical structure search tool and pre-load the structure into an editing tool.

Calculated Physical-Chemical Properties - Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand:

Number of Hydrogen Bond Acceptors
Number of Hydrogen Bond Donors
Number of Rotatable Bonds
Molecular Weight
Topological polar surface area: Polar surface area (PSA) is defined as the surface sum over all polar atoms (usually oxygen and nitrogen), including also attached hydrogens. Topological polar surface area is a useful parameter (molecular descriptor) employed for optimising cell permeability by medicinal chemists. It is generated by a computation of functional group contributions. For details on the methodology used see
Ertl, P., Rohde, B., and Selzer, P. (2000) Fast calculation of molecular polar surface area as a sum of fragment based contributions and its application to the prediction of drug transport properties. J. Med. Chem. 43, 3714–3717.
XLogP: Log of partition coefficient (LogP) is the logarithm of the ratio of concentrations of un-ionized compound between two solutions (octanol and water). The prediction of LogP is based on the atom-type method called XLogP as implemented in KNIME. For details of the methodology see
Wang, R., Fu, Y., and Lai, L. (1997) A New Atom-Additive Method for Calculating Partition Coefficients. Journal of Chemical Information and Computer Sciences. 37, 615-621.
No. Lipinski's rules broken: Lipinski's Rule of Five is a rule of thumb to evaluate ‘druglikeness’, or determine if a chemical compound with a certain pharmacological or biological activity has properties that would make it a likely orally active drug in humans. For further details see
Lipinski, C.A., Lombardo, F., Dominy, B.W., and Feeney, P.J. (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Del Rev. 23, 3–25.

Classification - Compounds are assigned to the following general classes based on their origin and structural properties:

Synthetic compounds: Low molecular weight, non-polymeric compounds produced via either total synthesis or semi-synthetic processes.
Small organic molecules: Low molecular weight, non-peptidic, biogenic compounds produced by life processes (normally endogenous and of animal origin) and their close analogues.
Natural products: Non-peptidic, biogenic compounds derived from living organisms and their close synthetic derivatives.
Peptides: Synthetic, semi-synthetic and natural peptides (oligopeptides and cyclic peptides).
Inorganic compounds: Ions and other inorganic compounds.
Others: Silicones and other non-carbon containing molecules and polymers.

IUPAC name - A systematic chemical name generated according to IUPAC rules using the NCI/CADD Chemical Identifier Resolver

Synonyms - Alternative names that exist in the literature.

Database Links - Provides the accession number and link outs for selected chemical databases, including PubChem, DrugBank, PharmGKB, ChEBI and PDB. CAS Registry Numbers are provided where known. CAS Registry Number is a Registered Trademark of the American Chemical Society.

Biological Activity - Tables of selectivity at receptors in the database, separated by receptor type (GPCR, ion channel) and by species. For full description see ligand table description above.

Structure Downloads - Various representations of the ligand 2D molecular structure, generated using Open Babel. These are:

SMILES (Simplified Molecular Input Line Entry Specification): A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification.
Standard InChI (IUPAC International Chemical Identifier) and InChI Key: InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChI Key is a simplified version of a full InChI, designed for easier web searching.

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