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Overview of ChEMBL Database. Gareth Owen, ChEBI group, EMBL-EBI Northwestern University 16 th October 2012. What is ChEMBL?. Open access database for drug discovery Freely available (searchable and downloadable) Content:

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overview of chembl database

Overview of ChEMBL Database

Gareth Owen, ChEBI group, EMBL-EBI

Northwestern University

16th October 2012

what is chembl
What is ChEMBL?
  • Open access database for drug discovery
  • Freely available (searchable and downloadable)
  • Content:
    • 2D structures & calculated properties (logP, MW, Lipinski, etc.)
    • Associated bioactivity data extracted from the primary medicinal chemistry journals such as J. Med. Chem.
    • Deposited data from neglected disease screening (e.g. malaria)
    • Subset of data from PubChem
  • Covers ~30 years of compound synthesis and testing
  • Annotated FDA-approved drugs
  • Secure searching (https://www.ebi.ac.uk/chembldb)
chembl database
ChEMBL Database

ChEMBL14

Targets: 9,003

Compounds: 1,376,469

Activities: 10,129,256*

Publications: 46,133

60% proteins

20% organisms

20% cell lines

* Includes:

~5,900,000 (PubChem)

~100,000 (Deposited malaria screening sets)

  • Assays are classified as:
    • Binding measurements
    • Functional assays
    • ADME/toxicity data

3

Content

chembl assays binding functional admet
ChEMBL Assays –Binding, Functional, ADMET

Binding Assays

  • Assays which directly measure the binding of a compound to a particular target
    • E.g., competition binding assays with a radioligand
  • Various endpoints measured, but most commonly reported are:
    • IC50 (half maximal inhibitory concentration)
    • Ki (binding affinity)
    • MIC (minimum inhibitory concentration)
    • % Inhibition (of activity)
functional assays
Functional Assays

Whole organism assays

(e.g., anti-infectives/parasitics)

Disease-derived cell-line

(e.g., human ovarian cancer cell line cytotoxicity)

Tissue or cell-based disease model

(e.g., glucose uptake by adipocytes)

Tissue or cell-based assay for target effect

(e.g., contraction of guinea-pig ileum)

Cell-based assay over-expressing target

(e.g., GPCR calcium mobilisation)

Target association

Disease association

admet assays
ADMET Assays
  • Assays measuring: Absorption, Distribution, Metabolism, Excretion, Toxicity properties of compounds
  • Examples include:
    • Half-life of compound in rats
    • Tissue distribution of compound
    • Levels of metabolites
chembl targets
ChEMBL Targets:

Protein Protein complex Protein family Nucleic Acid

e.g., DNA

e.g., Muscarinic receptors

e.g., Nicotinic acetylcholine receptor

e.g., PDE5

Cell Line TissueSub-cellular Fraction Organism

e.g., Nervous

e.g., HEK293 cells

e.g., Drosophila

e.g., Mitochondria

protein targets
Protein Targets
  • Each protein target linked to a sequence in UniProt
  • Information from UniProt used in ChEMBL to allow searching:
    • Protein name/description
    • Synonyms and gene names
    • Organism (and NCBI Tax ID)
  • Proteins in ChEMBL also classified according to family (e.g., Receptor, Kinase, Protease, Transporter etc).
    • Used for searching by target tree (Browse Targets)
c hembl compounds
ChEMBL Compounds
  • Tautomers of the same compound are treated as the same compound. The form shown is as in the paper
  • Chemical structures are stored as .mol files
  • If the stereochemistry is known it is drawn as a specific enantiomer
  • Identifying unique compounds is done using standard Inchis
  • Salts and parent molecules are grouped together for displaying bioactivity data although activity data is recorded against the specific salt
chembl home page
ChEMBL Home Page

https://www.ebi.ac.uk/chembldb

slide12

Drug Information

Clickable structure

Parent and Salt Forms

Small molecule resources at the EBI

slide14

Click to

display data

chemspider links
ChemSpider Links:

The link works both ways. They link TO ChemSpider and FROM ChemSpider.

They link on Standard_Inchi

wikipedia links
Wikipedia Links:

We also have links with Wikipedia. These also use the Standard_Inchi as the common identifier. These links will link to the Compound Report Card in ChEMBL.

The links are added by a ChemoBot and can be updated with each release, if required.

use case 1 searching by target
Use Case 1 - Searching by Target
  • What is known about chemical structures that bind to a specific protein (Adenosine A2a)?
  • What is known about their potency/selectivity/ADMET Properties
  • Is there any protein structure data?
use case 1 searching by target in chembl
Use Case 1 Searching by Target in ChEMBL

Choose Sources to include in search

retrieving bioactivity data single target
Retrieving Bioactivity Data - Single Target

3D Structures

Bioactivity data for target

Display all bioactivity data for target

Assay data for target

Click pie chart to retrieve particular end-points

filtering bioactivities
Filtering Bioactivities

Select targets of interest

Select required activity types and define cut-offs e.g Ki<100nM

bioactivity results
Bioactivity Results

Compound structures

Activity values

Assay details

Target details

References

selectivity data
Selectivity Data

For example:Can search ChEMBL for all data on compounds that have adenosine A2a Ki values <100nM

admet data
ADMET Data

Summary of ChEMBL bioavailability data for compounds with A2a Ki values <100nM

Example of Bioavailability data

use case 2 searching by structure
Use Case 2 – Searching by Structure

What compounds contain a particular substructure?

What is known about their bioactivities?

Known drugs/clinical Trials

slide29

name

Lists of Identifiers

  • Types of synonyms:
  • Research codes
  • Trade names
  • INN, USAN

Different sketchers

similarity and substructure searching
Similarity and Substructure Searching

Display/Download Bioactivity Data

filtering data on lipinski properties etc
Filtering Data on Lipinski Properties etc

Display Bioactivities of subset

32

slide32

names

Bioactivities

Structure

slide33

Properties

Cross-references

Clinical Trials

Bioactivities

links to other resources1
Links to Other Resources

PDBe - http://www.ebi.ac.uk/pdbe

marketed drugs
Marketed Drugs

Select set of interest

Export to Excel or

Export SDF

use case 3 similar targets
Use Case 3 – Similar Targets

Are there any available data on compounds that bind to proteins similar to IRAK2?

For these compounds what bioactivity data is there on compounds with related sub-structures?

Is there any crystal structure data on these proteins?

protein sequence search
Protein Sequence Search
  • *Altschul SF et al., J Mol Biol. 215(3), p403-10 (1990)
  • More precise method for identifying targets
  • Input is a protein sequence of interest
  • Uses BLAST* algorithm to perform pair-wise comparisons between input sequence and all proteins in the Target Dictionary, to find most closely related matches
  • Results are scored according to similarity to input sequence (determined by number of amino acids that are identical or have similar properties)
use case 3 similar targets1
Use Case 3 – Similar Targets

Protein Sequence of Interest e.gfrom UniProt

http://www.uniprot.org

Data on IRAK1,IRAK3 and IRAK4 but not IRAK2

slide40

IRAK1, IRAK3 and IRAK4 data

Identify sub-structure of interest

What other data available on compounds with this sub-structure?

use case 4 assay keyword search
Use Case 4 - Assay keyword search
  • Some ChEMBL data (e.g., functional assays) may not be mapped against molecular targets
  • May want to perform a more general search (e.g., for a disease process, animal model, cell type of interest)
  • Examples:
    • What compounds have been tested in disease models (cholesterol lowering)?
    • What data is available for brain penetration (brain to plasma ratio)?
useful links
Useful Links

ChEMBL Blog:

http://chembl.blogspot.com

If you would like help:

chembl-help@ebi.ac.uk

For ChEMBLnews and data releases subscribe to:

http://listserver.ebi.ac.uk/mailman/listinfo/chembl-announce

acknowledgements
Acknowledgements

ChEMBL Group

John Overington

Anne Hersey

Anna Gaulton

Mark Davies

Jon Chambers

Louisa Bellis

Kazuyoshi Ikeda

Patricia Bento

Shaun McGlinchey

Yvonne Light

Felix Krueger

Ben Stauch

Ruth Akhtar

Francis Atkinson

Rita Santos

EMBL-EBI

Samuel Kerrien, Sandra Orchard, Bruno Aranda, Rafael Jimenez, Reactome, UniProt and ChEBI teams

Collaborators

Imperial Cancer Research, University of Dundee, University of Cambridge, Sanger Centre, University of Maryland, NCBI, TDR, IUPHAR, Bayer-Schering, Pfizer, GSK, Schering-Plough, MMV, Novartis, St Jude Children’s Research Hospital

Former Inpharmatica colleagues