Post on 11-May-2015
description
Sourcing High-Quality Online Data Resources for Computational Toxicology
Antony WilliamsBio-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 toServe 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?
What is the Structure of Vitamin K1?
CAS’s Common Chemistry
Wikipedia
ChEBI – Manual Curation
PubChem
“2-methyl-3-(3,7,11,15-tetramethylhexadec-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
Wow!
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
Vytorin: Ezetimibe/Simvastatin
Vytorin: Ezetimibe/Simvastatin
Vytorin: Ezetimibe/Simvastatin
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 ChemSpiderCAS Com.
Chem ChemIDPlus DailyMed DrugBank PubChem Wikipedia
SpirivaTiotropium Bromide
No Hits No Hits 4/0
DepakoteValproate 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”
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 Source and Data
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: ChemConnectorBlog: www.chemspider.com/blogPersonal Blog: www.chemconnector.comSLIDES: www.slideshare.net/AntonyWilliams