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)
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…
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
I used the InChI String to search ChemSpider and found it here.
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:
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?
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.
Compare the name generated by ACD/Name using the INDEX name generation
The_interface below shows the name in the software interface.
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.