1.
Towards a Gold Standard: Improving The
Quality of Public Domain Chemistry
Databases
Antony J. Williams1, Sean Ekins 2
1Royal Society of Chemistry, Wake Forest, NC 27587
2Collaborations in Chemistry, Fuquay Varina, NC 27526.

2.
The future: crowdsourced drug discovery
Williams et al., Drug Discovery World, Winter 2009

3.
Chemistry structures are proliferating
on the web
 Safety data
 Toxicity data
 Blogs and Wikis
 Property databases Users take them at face value
 Experimental results
 Scientific publications They SHOULD NOT!!!
 Compound aggregators
 Open Notebook Science
 Metabolic pathway databases
 Encyclopedic articles (Wikipedia)
Immense quantities of scientific information are contained in the
thousands of databases
Progress can however be inhibited by errors in these databases,
downstream effects when the data is reused.
http://bit.ly/zWGaps

4.
What is the Structure of Vitamin K1?

5.
What Mechanisms Do we Have to Alert the Community ?
 Email database owner and hope for a response
 Blog it
 Tony has been blogging about database quality for years and nobody
was listening – other than the people at PubChem
 For some databases, when he blogged they listened and would edit!
 Tweet it
 Dec 2010 - We felt something had to be said definitively about structure
quality
 Publish it – wrote to Science, Nature and then PLoS Computational Biology
http://bit.ly/qtJF2f
Perhaps the phone?

6.
April 27 2011- Then came the :
The NPC Browser
Science Translational Medicine 2011

7.
But wait, hold on – did anyone peer review the
database??
Database released and within days ..
A quick analysis of structure quality revealed..
100’s of errors found in structures
Williams and Ekins,
DDT, 16: 747-750 (2011)

8.
NPC Browser
http://tripod.nih.gov/npc/

9.
Neomycin in NPC Browser
http://tripod.nih.gov/npc/

10.
Neomycin In ChemSpider

11.
How many contribute to
clean-up?
 Less than a dozen contributors to data
 The majority are project members
 The crowd is small…
 This is the same for all cheminformatics crowd-
based efforts

12.
What Mechanisms Do we Have to Alert the Community –
Publishing is too slow
 Tony Blogged April 28th 1 day after
release http://bit.ly/jn8wLC
 I Blogged April 29th http://bit.ly/lXHInG
 suggesting the need for a gold standard
database
 After more extensive analysis we sent a
manuscript to Science Translational
Medicine - Rejected
 Drug Discovery Today..accepted…8
Months after we pointed out the issue
even before NPC Browser release..
Williams and Ekins,
DDT, 16: 747-750 (2011)

13.
Responses from Community and NCGC
 Comments on initial blog
 NCGC added a disclaimer which I blogged about May 23rd
http://bit.ly/m4Tx2b
Sept 8th 2011
Email from Tudor Oprea
(cc’ed to 60 others)
He has also been pointing
out database errors for
years..
Followed by one from
Chris Austin offering to
meet us
Several individuals thanked us for the alert

14.
More Extensive Analysis and solutions
 More analysis of NPC browser errors
 “analysis of the NPC browser ‘HTS amenable compounds’ subset of
data for 7600 compounds identified fundamental errors in
stereochemistry, valency issues and charge imbalances in a few
minutes work using a rudimentary software tool”
 Analysis of other chemistry databases and errors
 Other types of databases and errors
 Offered solutions
Towards a Gold Standard: Regarding Quality in Public Domain Chemistry Databases and Approaches to Improving
the Situation Antony J. Williams, Sean Ekins and Valery Tkachenko, Drug Discovery Today, In Press 2012

15.
Data Errors in the NPC Browser: Analysis of Steroids
Substructure # of # of No Incomplete Complete but
Hits Correct stereochemistry Stereochemistry incorrect
Hits stereochemistry
Gonane 34 5 8 21 0
Gon-4-ene 55 12 3 33 7
Gon-1,4-diene 60 17 10 23 10
Towards a Gold Standard: Regarding Quality in Public Domain Chemistry Databases and Approaches to Improving
the Situation Antony J. Williams, Sean Ekins and Valery Tkachenko, Drug Discovery Today, In Press 2012

16.
Why this matters to us and
YOU the CROWD ?

17.
What You Might Not Know About
Chemistry Databases On The Internet
 Data-sharing between open databases is cyclic
 This can proliferate errors in the “Linked Data”

18.
Public Domain 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 and challenging

19.
Molecule Data Quality Impacts
 in silico drug discovery
 vast ligand and protein–protein interaction databases
 develop computational models
 global mapping of pharmacological space
 drug-target networks of approved drugs
 prediction of off-target effects

20.
Different types of
databases and errors
 Bayer paper on target validation 2/3 of papers did not live up to claims
 MDL Drug Data Report (MDDR), errors
 Errors in clinical research databases vary from 2.3% to 26.9%
 Multicenter analysis by MS-based proteomics identified generic problems in
databases when characterizing proteins -search engines could not distinguish
different identifiers many algorithms calculated molecular weight incorrectly
 One database had between 2.1% and 13.6% of annotated Pfam hits unjustified
 ligand–protein X-ray structure - these can also have errors with far reaching
consequences

21.
Solutions
 Structure Validation and Standardization
 Curation
 Annotation
 Structure filters
 Incorrect valency, atom labels, aromatic bonds, stereochemistry, salts,
duplication
 Structure standardization guidelines
 Provided by the FDA (Substance Registration System UniqueIngredient
Identifier (UNII):
http://www.fda.gov/ForIndustry/DataStandards/SubstanceRegistrationSyste
m-UniqueIngredientIdentifierUNII/default.htm)
 Need a record of molecule provenance
 Can we track databases and quality - - www.scidbs.com

22.
RSC Introduces “Validation Service”

23.
Scidbs.com
Default Body

24.
Scidbs.com
DB logo
Type of DB
Contact
Owner
Default Body Website
License
Curation etc

25.
Data should be:
 Free from structure errors
 Free from data errors
 Free from experimental errors
 Are we asking too much? Is it even possible??
Yet when we alert others:
 When we raise our hands we are ignored
 Our scientific community needs to wake up

26.
Today
 NPC browser has fewer errors..so do ALL databases!
 More people aware of molecule quality online. Trust is
earned not just granted!
 The future database user is more informed
Tomorrow
 Peer reviewers test the databases that are in manuscripts
 NIH checks databases before release!
 COLLABORATION between government DBs. PLEASE!!!
 We need minimal compound database standards
(MCDS)

27.
Acknowledgement
We thank the paper reviewers
and blog commenters
for their constructive comments
Chris Lipinski
This work was unfunded
(but was the right thing to do!)
www.scidbs.com