Data Quality in the NCGC Pharmaceutical Collection Browser Part 4

08 May

I am now back in the US after a week in Europe and late at night, with a disrupted sleep pattern and looking for something to soothe me to sleep I have been wandering through the rest of the NPC Browser data set [1,2,3] looking for more patterns in the data to see if I can come up with some general advice and cautions about how to build datasets of chemistry. I already have my “conclusion” in my head as to the best advice I can give to any government organization, and others, who are trying to build chemical databases but I will save this for later in the week. For now I want to highlight some of the issues to be careful of. Tonight’s focus is “structural depictions”.

Achieving high quality algorithmic 2D structural layout is difficult across large databases is difficult. All of the cheminformatics vendors have layout tools whereby a structure can be “cleaned” so that the layout on the page is visually appealing. If you have ever used any of the cleaning tools you might have discovered that they fail dismally with certain structures and you have to perform a layout manually. You might have discovered that when you clean the structure that stereocenters flip (something that should NEVER happen but, believe me, does!) However, there are some good tools that are available. OpenEye provide layout algorithms as part of their cheminformatics toolkit and it is certainly one I have experience of.

In any case, when creating a database of chemicals it makes good sense to use algorithms for layout rather than accept what is submitted. PubChem and ChemSpider, with tens of millions of structures, have to use algorithmic cleaning but if you have a small database it won’t take long to visually inspect and spot errors very quickly. There are many examples that SHOULD have been caught with the recent NGC HTS screening set.

The worst one of these that I found while simply browsing was that associated with “Silidianin” as shown below.

The "0D" Structure of Silidianin in the NPC Browser

Here we see the structure of a bare hydroxyl group, but without a negative charge. However, the CAS number and various synonyms certainly don’t support the compound being a hydroxyl group. Indeed, this is a “0D structure” with all xy coordinates set to 0,0 and if the structure is cleaned in a drawing package then you see the structure shown on the left below. While it is the connection table for Sildianin it does not have the appropriate stereochemistry for Sildianin encoded into the structure with wedge and dashed-wedge bonds. The structure on the right has that shown.

Silidianin: Left Structure is Cleaned and Right Structure is with Stereocenters Added

I think you would agree it is more aesthetically pleasing and does communicate the bridged nature of the compound and carries the stereochemical information. However, there is something wrong with even this picture. Can anyone say what’s wrong?

Accurate structural representation in any database takes time, effort and, often, a skilled and careful eye to get right. Clearly the 0D structure is simply wrong and should have been caught. There are other offenders in the database that should have been caught also as shown below. There are LOTS more.

Various Examples of Structures Requiring Layout Improvements

Building high quality chemical databases certainly is tricky…and can be very time-consuming to solve all of these issues.



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 ( 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 (, 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 ( and the RSC lead for the PharmaSea project ( 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, 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.

One Response to Data Quality in the NCGC Pharmaceutical Collection Browser Part 4

  1. Dave

    May 11, 2011 at 6:10 am

    Hi Tony,

    I see the issue with your representation of Silidianin – I won’t explicitly point it out (Hint to everyone else: look closely at the stereocentres). Looking at ChemSpider – we are currently no better (at the time of writing 11/05/2011: a name search returns CSID 2298521 and 10752061 – though I’ll try to curate these soon).

    I think that there are 2 points to be made (both of which I know that you are aware of), which are around the human vs the machine interpretation of structures:

    1. Depiction of stereobonds
    In most drawing packages when you use a wedge bond – the narrow end of the wedge is considered to be at the stereocentre. However, not all chemists use that convention – and in “many” cases a human can still interpret what is meant unambiguously. This ability of humans to “fill in the blanks” is also the reason why (I would suggest) it is easy to miss the error in the structure of Silidianin.

    2. Appropriate use of stereobonds for machine processing
    Where structures have stereochemical features that cannot be easily “flattened out” into a 2D structure there is potential to use stereobonds incorrectly. Technically, they should only be used in 2D representations, any representation where perspective is involved and there is no longer a clearly defined plane with which you can reference wedges as “coming out of” or “going away from” is prone to error. In such cases it is possible to draw structures that are aesthetically pleasing (and understandable) to a human – but are not always processed correctly by software algorithms. To illustrate my point I would direct you to the structure of (DHQ)2PHAL (
    Such structures are very time consuming to draw – to depict in a way that fulfills the criteria of being:

    1. understandable by humans
    2. processable by software – with fully defined stereochemistry
    3. the software processed representation having captured the stereochemistry at all centres correctly.

    Just as we would probably build molecular models to properly understand such structures when reading a paper – I am finding more an more that 3D molfiles are useful for properly capturing complex structures.


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