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Will the Correct Structure of Taxol Please Stand Up. Part 3.

27 Sep

This is part 3 (1,2) in the mission to correctly identify the structure of Taxol. I’ve gone on the mission to identify the correct structure after noticing the contradiction via the Wikipedia page commentary PMR made earlier this week. As commented in Part 2 there is a direct contradiction in the two molecules linked off of Wikipedia…one linked to Drugbank and one linked to PubChem. My question is, which one is right? And if neither of them is correct, is the one in Wikipedia correct. And, if that isn’t correct what IS the structure of Taxol.

I posted a request to CHMINF-L today with a link to the earlier blog postings defining the issue. I received a lot of suggestions and guidance. These included:

1) Check PubChem for the structure of Taxol. (Ahem…check out my statement regarding I don’t know which is right!)

2) I got pointed to the C&E News story …very useful by the way

3) I received a link to the structure for Taxol as found in the MDL Compound Index on the DiscoveryGate platform. The CASRN of 33069-62-4 is associated with this structure in a variety of databases including Beilstein, MDL Available Chemicals Directory, MDL Toxicity, PubChem, PharmaPendium, xPharm and others.

4) I received a link to the structure of Taxol on DTP . This is the Developmental Therapeutics Program of the NCI.

5) I received directions about how to use STN-Easy and get the structure and the CAS number/synonyms etc for just a few dollars.

Using point 5 as a basis let’s start HERE and set this as the actual structure of Taxol. Let’s work from the point of view that THIS is highly curated data and is correct. It is an assumption but we need to start somewhere. The image is shown below and I hope that I haven’t broken “image copyright” posting it here (I’ve been watching all the discussions about this by PMR but am taking the risk nevertheless)

STN structure

Now, I happened to have used Taxol as an example in the Chapter I wrote in the Third Edition of the ACS Style Guide. It’s a good example of the challenges of structure representation, stereochemistry and systematic nomenclature. When I wrote that article I used the structure taken from the ACD/Dictionary included with the commercial version of ACD/ChemSketch (at that time I was the product manager so I had easy access to the tool. in fact, the webpage advertising the ACD/Dictionary uses Taxol!

So, imagine my concern in wanting to compare the STN structure with the ACD/Dictionary structure…results below..deep breath…

ACD/Dictionary

The structure is identical, in terms of connectivity and stereochemistry, to that from STN Easy (but, in my opinion, much more attractive. Since STN doesn’t give me an InChI (which strikes me as strange when many of us in the domain support the shift and the industry will demand it shortly!) I will generate the InChI inside ACD/ChemSketch and work from there.

The InChI String is: InChI=1/C47H51NO14/c1-25-31(60-43(56)36(52)35(28-16-10-7-11-17-28)48-41(54)29-18-12-8-13-19-29)23-47(57)40(61-42(55)30-20-14-9-15-21-30)38-45(6,32(51)22-33-46(38,24-58-33)62-27(3)50)39(53)37(59-26(2)49)34(25)44(47,4)5/h7-21,31-33,35-38,40,51-52,57H,22-24H2,1-6H3,(H,48,54)/t31-,32-,33+,35-,36+,37+,38-,40-,45+,46-,47+/m0/s1/f/h48H

and the InChIKey is: RCINICONZNJXQFMZXODVADBJ

I used the InChI String to search ChemSpider and found it here.

taxol.png

While Taxol is on Chemspider 7 times only this one record is the ACTUAL structure. One of the 7 is the incorrect structure just based on molecular formula (there are two data sources for this deposition: one from PubChem and one from ChemBlock). For the other 6 structures all have the SAME connectivities but the stereochemistry is different. This is crystal clear in the new InChIKey comparison as shown below:

RCINICONZNJXQF-CLDWUXIMDD

RCINICONZNJXQF-SWYDOUDSDE

RCINICONZNJXQF-XIKKIZKTDF

RCINICONZNJXQF-GXKQXQCDDN

RCINICONZNJXQF-MZXODVADBJ

RCINICONZNJXQF-LOQTUHTGBW

Notice the first 14 characters are consistent…but the stereo layer is different. So,where does this get us with the Wikipedia entry shown below?

Wikipedia

I can confirm at this point the CAS Number is correct. Comparing the structure we have identified as correct with that on Wikipedia here I can confirm the structure on Wikipedia IS Correct. Yay. The link to the PubChem record is to the correct an INCORRECT structure and should be edited to linked to CID:36314 . The structure on DrugBank is CORRECT.

Now, what about the one sent to me by MDL and displayed here? It is CORRECT.

What about Taxol on DTP? I reviewed the 2D structure on the site but could not download it as a molfile. I would have had to download the entire 50Mbyte file. I downloaded the SMILES string and converted but it had no stereochemistry. So, I searched the ID number NSC125973 in PubChem since the DTP data is deposited there. The PubChem structure identified is 36314, the one in the Wikipedia DrugBox and the CORRECT structure.

What about Taxol in the C&E News story? The structure is CORRECT.

So, we know what the correct structure is…someone needs to confirm my findings and make the edit in Wikipedia please!

Ok, let’s look at systematic names for Taxol names. There are so many variants and I really do have to question their quality!

This is not a systematic name for taxol in my opinion: 7,11-Methano-5H-cyclodeca[3, 4]benz[1,2-b]oxete,benzenepropanoic acid deriv.

Let’s look at the C&E News name here and shown below.

C&E NEws name

Compare the name generated by ACD/Name using the INDEX name generation

Index Name Text

The_interface below shows the name in the software interface.

IndexName

Here_again we see a complication…the name in the C&E News article and the ACD/Name software differ in the stereo definitions in the block: (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS). The 4aS in ACD/Name is 4bS in the article. I am working to figure out the difference here right now.

PMR commented in a recent blog post “Naming is hard. Very hard. It’s been said that there are only two hard problems in computer science and naming is one of them.” I spent ten years at ACD/Labs working hard with some of the most skilled nomenclature specialists in the industry to make it simpler for chemists to generate systematic names. Would you want to MANUALLY name the structure above…really? There are many other systematic naming tools out there today from Cambridgesoft, ChemAxon, OEChem and others. I recommend using them!!! They can be very capable and include organometallics, some of the most challenging complexes to name.

What’s the bottom line about Taxol? Here’s the point…overall PMR was right about the fact that Wikipedia is highly curated. But not perfect. While the link to PubChem is to the wrong structure the right structure IS on PubChem…care must be taken to identify issues like this..more curation is required.

My biggest comment is that the quality of repositories such as PubChem and ChemSpider is going to degrade if there is no curation effort and if anybody and everybody is starting to deposit their data either as massive SDF deposits or as singletons. Curation efforts are essential.

 

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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Posted by on September 27, 2007 in ChemSpider Chemistry

 

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