Sourcing high quality online data resources for computational toxicology

Sourcing High-Quality Online Data Resources for Computational Toxicology Antony Williams Bio-IT World, Current Methods for Computational Toxicology and Chemogenomics

The Community Depends On Us
“ We don’t want another Love Canal!”
“ What we know about PCBs should warn us all!”
The public is “suspicious” of pharma…
“ Chemicals are dangerous”

Comp Tox Models Depend on DATA
Models for Computational Toxicology depend on the quality of the training set
There are multiple issues with data quality including:
Experimental
The validity of the method, Reproducibility, Sample quality, Data capture, Transcription of values
Computational
Accurately representing the data – correct units, annotations, quality flags, attribution, are the structures correct?

Nothing but the Facts
Jean-Claude Bradley, Drexel University
“ There are no facts, only measurements embedded within assumptions”

Open Notebook Science
UsefulChem Blog: http://tinyurl.com/48dyujh

Aqueous Solubility of ECGC
Epigallocatechin gallate solubility in water

Melting Point of DMT

Content is King and Quality Costs
Chemistry “content” is big money
Patent searching
Structures and properties
Drug databases
Literature databases
Chemical Abstracts Service (CAS), the “Gold Standard” in Chemistry related information
101 years of content
$260 million revenue (2006)
>50 million substances
>60 million sequences

Where can we find data online?

Where is chemistry online?
Encyclopedic articles (Wikipedia)
Chemical vendor databases
Metabolic pathway databases
Property databases
Patents with chemical structures
Drug Discovery data
Scientific publications
Compound aggregators
Blogs/Wikis and Open Notebook Science

Lots of “Public Compound” Databases
PubChem
Drugbank
ChEBI/ChEMBL
KEGG
LipidMAPs
ChemIDPlus
eMolecules
ZINC
Lots of chemical vendors
ChemSpider

Toxicology Data

Chemistry on the Internet
ChemSpider “links” chemistry on the internet
Almost 25 million compounds, 400 data sources
Allows community deposition, curation, annotation
Integrating properties, publications, patents, media
Text, structure and substructure searching

www.chemspider.com

Search for a Chemical

Available Information…
Linked to vendors, safety data, toxicity, metabolism

We Have Delivered the Vision
“ Build a Structure Centric Community to
Serve Chemists”
Integrate chemical structure data on the web
Create a “structure-based hub” to information, data and algorithmic predictions
Let chemists contribute their own data
Allow the community to curate/correct data

Dialects describing chemicals

What is the Structure of Vitamin K?

MeSH
A lipid cofactor that is required for normal blood clotting. Several forms of vitamin K have been identified: VITAMIN K 1 (phytomenadione) derived from plants , VITAMIN K 2 (menaquinone) from bacteria, and synthetic naphthoquinone provitamins, VITAMIN K 3 (menadione). Vitamin K 3 provitamins, after being alkylated in vivo, exhibit the antifibrinolytic activity of vitamin K. Green leafy vegetables, liver, cheese, butter, and egg yolk are good sources of vitamin K

What is the Structure of Vitamin K1?

CAS’s Common Chemistry

Wikipedia

ChEBI – Manual Curation

PubChem

“ 2-methyl-3-(3,7,11,15-tetramethyl hexadec-2-enyl)naphthalene-1,4-dione”
Variants of systematic names on PubChem
2-methyl-3-[(E,7R,11R)-3,7,11,15-tetramethyl
2-methyl-3-[(E,7S,11R)-3,7,11,15-tetramethyl
2-methyl-3-[(E,7R,11S)-3,7,11,15-tetramethyl
2-methyl-3-[(E,7S,11S)-3,7,11,15-tetramethyl
2-methyl-3-[(E,11S)-3,7,11,15-tetramethyl
2-methyl-3-[(E)-3,7,11,15-tetramethyl
2-methyl-3-(3,7,11,15-tetramethyl
2-methyl-3-[(E)-3,7,11,15-tetramethyl

Public Domain Chemistry Databases
Our databases are a mess…
Non-curated databases are proliferating errors
We source and deposit data between databases
Original sources of errors hard to determine
Curation is time-consuming, challenging and exacting

Vancomycin
Who will curate?
PubChem is not resourced to clean these errors
How would you clean such a large dataset?

The FDA’s DailyMed

Structures on DailyMed

Lack of Stereochemisty

Incorrect Structures

We want to model DILI…
Drug metabolism in the liver can convert some drugs into highly reactive intermediates,
This can affect the structure and functions of the liver.
Drug-induced liver injury (DILI), is the #1 reason drugs are not approved and withdrawn from market after approval
Estimated global annual incidence rate of DILI is 13.9-24.0 per 100,000 inhabitants
DILI accounts for an estimated 3-9% of all adverse drug reactions reported to health authorities
Herbal components can cause DILI too
Thanks to Sean Ekins https://dilin.dcri.duke.edu/for-researchers/info/

Initial DILI data – Names and Data
Griseofulvin
Hycanthone
Hydrochlorothiazide
Hydrocortisone
Hydroxyurea
Idarubicin HCl
Idoxuridine
Imipramine HCl
indomethacin
isoniazid
Isoproterenol HCl
Isotretinoin
Isoxsuprine HCl
Kanamycin Sulfate
Ketorolac Tromethamine
Ketotifen
Labetalol

So you want data on drugs???
Sourcing data based on drug names is difficult!
Where would you find the “correct chemical structures”?
What databases can you trust?

Vytorin: Ezetimibe/Simvastatin

Symbicort: Budesonide + Formoterol

Symbicort: Budesonide + Formoterol ChemIDPlus Wikipedia

DrugBank: Search Symbicort…

Symbicort: Budesonide + Formoterol
PubChem
8 structures called Budesonide. 1 “correct”
6 structures called Formoterol. 1 “correct”
Search on “Symbicort” gives 1 structure.

Taxol: Paclitaxel 44 structures

Taxol: Paclitaxel Bioassay Data

Public Domain Chemistry Databases
An examination of quality in databases – inter/intra lab comparison of processes for 150 drugs

Drug Name Generic Name ChEBI ChemSpider CAS Com. Chem ChemIDPlus DailyMed DrugBank PubChem Wikipedia Spiriva Tiotropium Bromide No Hits  No Hits    4/0  Depakote Valproate semisodium        No Structure Basen Voglibose   No Hits  No Hits  2/1  Symbicort 1) Budesonide       8/1  Symbicort 2) Formoterol WRONG  No Hits    6/1  Vytorin 1) Ezetimibe   No Hits      Vytorin 2) Simvastatin       2/1  Taxol Paclitaxel       44/1  Thalidomid Thalidomide No Hits        Zocor Simvastatin       2/1  Crestor Rosuvastatin   No Hits    2/1 

Personal Experiences
Highest Quality Resources : DSSTox (EPA), ChEBI (EBI)
High Quality Resources : DrugBank, Human Metabolome Database, ChemIDPlus, ChemSpider, KEGG
Are there others you use???

What can be done to help?
“ Crowdsourcing” – gather the support of members of the community to add, annotate and curate data
Wikipedia is the domain success story for crowdsourcing.
PubChem is an example of “crowdsourced deposition” of chemistry data
ChemSpider is an example of “crowdsourced deposition and curation”

The Future: Open Source and Data
Open source software : descriptors and algorithms
QSAR should be cheaper and better!
Selectively share your models with collaborators
Centralized hosting of models / predictions

The Future: Open PHACTS
The Open PHACTS project will develop an open access innovation platform, called Open Pharmacological Space (OPS), via a semantic web approach. OPS will be comprised of data, vocabularies and infrastructure needed to accelerate drug-oriented research.

Exposing Data for Semantic Web…

Coming soon…
Book chapter:
“ Accessing, Using and Creating Chemical Property Databases For Computational Toxicology Modeling ”
Antony J. Williams, Sean Ekins, Ola Spjuth and Egon L. Willighagen

Thank you Email: williamsa@rsc.org Twitter: ChemConnector Blog: www.chemspider.com/blog Personal Blog: www.chemconnector.com SLIDES: www.slideshare.net/AntonyWilliams

Sourcing high quality online data resources for computational toxicology

by Antony Williams, ChemConnector on Mar 29, 2011

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Sourcing high quality online data resources for computational toxicology Presentation Transcript