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Duplicate compounds in the NPC Browser and NCGC Dataset

26 Jul
I am presently working on a couple of articles, book chapters and guest blog posts regarding quality in public domain chemistry databases. In so doing I have continued to work through the data contained within the NPC Browser that I have blogged about many times before. I HAVE been adding curation comments to the data as I have worked through them and have removed inappropriately associated chemical names. Eventually it became too much of a burden relative to me getting my work done as there are so many edits required. What I have been looking for specifically is examples of what I thought would exist in the database – that of a failure to deduplicate. Deduplication, in terms of chemistry databases, is collapsing together records based on the same chemical structure. This sounds easy but it isn’t necessarily so….consider some of the complexities of collapsing tautomers. SIMPLE collapsing can be done by generating InChIKeys and deduplicating but InChI tautomer detection is imperfect and this approach will fail regularly. The majority of the cheminformatics toolkits have their own ways of generating fingerprints to deal with this issue of deduplication.

While browsing the database I came across Ranitidine, the active component of the well known drug Zantac. I found two records in the database. They are shown below and numbered as 1/2 and 2/2.

Ranitidine record 1.

Ranitidine record 2.

I have compared these records as molfiles. I have compared SMILES string (below).

CN\C(NCCSCC1=CC=C(CN(C)C)O1)=C/[N+]([O-])=O
CN\C(NCCSCC1=CC=C(CN(C)C)O1)=C/[N+]([O-])=O

I have compared InChIs

InChI=1S/C13H22N4O3S/c1-14-13(9-17(18)19)15-6-7-21-10-12-5-4-11(20-12)8-16(2)3/h4-5,9,14-15H,6-8,10H2,1-3H3/b13-9+
InChI=1S/C13H22N4O3S/c1-14-13(9-17(18)19)15-6-7-21-10-12-5-4-11(20-12)8-16(2)3/h4-5,9,14-15H,6-8,10H2,1-3H3/b13-9+

VMXUWOKSQNHOCA-UKTHLTGXSA-N
VMXUWOKSQNHOCA-UKTHLTGXSA-N

Try as I might I don’t see a difference between these structures. Why were they not deduplicated? This leads to the question how many more duplicates are in the database and why? I have no idea….just an observation.

 

 

 

 

 

 

About tony

Antony (Tony) J. Williams received his BSc in 1985 from the University of Liverpool (UK) and PhD in 1988 from the University of London (UK). His PhD research interests were in studying the effects of high pressure on molecular motions within lubricant related systems using Nuclear Magnetic Resonance. He moved to Ottawa, Canada to work for the National Research Council performing fundamental research on the electron paramagnetic resonance of radicals trapped in single crystals. Following his postdoctoral position he became the NMR Facility Manager for Ottawa University. Tony joined the Eastman Kodak Company in Rochester, New York as their NMR Technology Leader. He led the laboratory to develop quality control across multiple spectroscopy labs and helped establish walk-up laboratories providing NMR, LC-MS and other forms of spectroscopy to hundreds of chemists across multiple sites. This included the delivery of spectroscopic data to the desktop, automated processing and his initial interests in computer-assisted structure elucidation (CASE) systems. He also worked with a team to develop the worlds’ first web-based LIMS system, WIMS, capable of allowing chemical structure searching and spectral display. With his developing cheminformatic skills and passion for data management he left corporate America to join a small start-up company working out of Toronto, Canada. He joined ACD/Labs as their NMR Product Manager and various roles, including Chief Science Officer, during his 10 years with the company. His responsibilities included managing over 50 products at one time prior to developing a product management team, managing sales, marketing, technical support and technical services. ACD/Labs was one of Canada’s Fast 50 Tech Companies, and Forbes Fast 500 companies in 2001. His primary passions during his tenure with ACD/Labs was the continued adoption of web-based technologies and developing automated structure verification and elucidation platforms. While at ACD/Labs he suggested the possibility of developing a public resource for chemists attempting to integrate internet available chemical data. He finally pursued this vision with some close friends as a hobby project in the evenings and the result was the ChemSpider database (www.chemspider.com). Even while running out of a basement on hand built servers the website developed a large community following that eventually culminated in the acquisition of the website by the Royal Society of Chemistry (RSC) based in Cambridge, United Kingdom. Tony joined the organization, together with some of the other ChemSpider team, and became their Vice President of Strategic Development. At RSC he continued to develop cheminformatics tools, specifically ChemSpider, and was the technical lead for the chemistry aspects of the Open PHACTS project (http://www.openphacts.org), a project focused on the delivery of open data, open source and open systems to support the pharmaceutical sciences. He was also the technical lead for the UK National Chemical Database Service (http://cds.rsc.org/) and the RSC lead for the PharmaSea project (http://www.pharma-sea.eu/) attempting to identify novel natural products from the ocean. He left RSC in 2015 to become a Computational Chemist in the National Center of Computational Toxicology at the Environmental Protection Agency where he is bringing his skills to bear working with a team on the delivery of a new software architecture for the management and delivery of data, algorithms and visualization tools. The “Chemistry Dashboard” was released on April 1st, no fooling, at https://comptox.epa.gov, and provides access to over 700,000 chemicals, experimental and predicted properties and a developing link network to support the environmental sciences. Tony remains passionate about computer-assisted structure elucidation and verification approaches and continues to publish in this area. He is also passionate about teaching scientists to benefit from the developing array of social networking tools for scientists and is known as the ChemConnector on the networks. Over the years he has had adjunct roles at a number of institutions and presently enjoys working with scientists at both UNC Chapel Hill and NC State University. He is widely published with over 200 papers and book chapters and was the recipient of the Jim Gray Award for eScience in 2012. In 2016 he was awarded the North Carolina ACS Distinguished Speaker Award.

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5 Responses to Duplicate compounds in the NPC Browser and NCGC Dataset

  1. trung

    July 28, 2011 at 12:09 am

    Hi Tony, this duplication is a result of curation. There should be tick marks on these two records to give you the change history as you mouse over. I don’t see them in your screenshots. This looks like a software bug. Here one of the structures (i.e., ranitidine bismuth citrate) wasn’t properly salt/solvent stripped (the standardizer removed citrate but not bismuth because it wasn’t in our salt/solvent look-up table). I suspect there will be a few more examples of this. These records will certainly be merged on our next database update. Thanks for reporting.
    Trung

     
  2. tony

    July 28, 2011 at 6:15 am

    Sorry Trung I am confused. I don’t see Bismuth associated with either of the records. Looking at the SMILES or downloading the molfiles doesn’t show the Bismuth so at the structure level these records are identical. The SMILES are copied directly from the browser
    CN\C(NCCSCC1=CC=C(CN(C)C)O1)=C/[N+]([O-])=O
    CN\C(NCCSCC1=CC=C(CN(C)C)O1)=C/[N+]([O-])=O

    I can take screenshots for you of the latest version I am running. They BOTH have green checkmarks.
    If the stripping happens prior to deposition, which it should, the records should collapse together. Am I missing something?

     
  3. trung

    July 29, 2011 at 12:05 am

    Hi Tony, prior to curation the structures for these two records were indeed different due to the bismuth component. After curation, the two structures converged. You can see this change by mouse over the tick mark in the upper right corner like seen here http://tripod.nih.gov/files/ranitidine.png (not sure why you don’t have these tick marks in your screenshots). Ideally, we should be able to automatically merge these two records once the second curation is submitted, but since we allow anyone to submit curation (anonymously or not), we can’t willy-nilly accept changes without looking over them. We just haven’t found the time to do this yet. I’ll be happy to go into details behind the scene of how we do registration if you’re interested. In fact, I did just that with John Hollerton a few weeks back on these very same compounds. I’m looking forward to his white paper addressing these thorny issues for Open PHACTS.
    Trung

     
  4. tony

    July 29, 2011 at 7:08 am

    Ok, that makes sense. I tried to look at your screenshot but the link didn’t work. I get a lot of issues on tripod.nih.gov links…the site seems down from my side quite regularly. Makes total sense that you cannot trust everyones curations! I assume that you will simply deprecate the Bismuth record? the Open PHACTS chemistry standardization team met in London two weeks ago and we have made good progress in defining a path forward for the standardization. I expect it will be a while before we issue the white paper though. Watch this space.

     
  5. John Hollerton

    November 18, 2011 at 3:13 am

    This is why I love using Zantac as a query against chemical databases. Almost inevitably there will be some arbitrary stereochemistry on the double bond (this moiety interchanges at room temperature so it should have mixed stereochemistry). The normal mismatch is between free-base and salt, often mixing terms as synonyms on the same record. In this particular case, both ranitidine HCl (Zantac) and ranitidine bismuth citrate will produce ranitidine base as the parent structure. This is correct although the bisumth citrate actually has a therapeutic active role. This becomes a grey area in representation as the normal assumption is that the salt form has limited biological significance. It just goes to show how tricky some of these issues are. I am encouraged to see that the synonyms are, however, internally consistent and there is no mixing of the zantac and tritec synonyms!

     

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