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Terminal Dimethyl means Death by Methane twice

When writing talks I try to find interesting (and where possible fun) examples of how challenging the world of managing chemistry data is for all of us that work in the world of managing 10s of thousands, or in our cases millions of compound pages for the community to use. I have told many stories over the past few years of the challenges we collectively have in regards to data quality and how it flows between our databases unabated. My latest example used at the recent talk at the EBI (ChemSpider – An Online Database and Registration System Linking the Web) was the structure known as Terminal Dimethyl presently on PubChem, DrugBankWolfram Alpha and PDBe. It was originally inherited into ChemSpider also but has been deprecated. I left a comment on DrugBank a couple of weeks ago but it hasn’t been published yet…generally such errors are removed VERY quickly by the DrugBank hosts. I added a comment to Wolfram Alpha and received a canned response and no changes to the record as yet.

There ARE ways to communally resolve these issues and I will blog about that shortly.

 
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Posted by on October 31, 2011 in Data Quality, Humor, Quality and Content

 

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Presentation at the 5th Meeting on U.S. Government Chemical Databases and Open Chemistry

Yesterday I gave a talk at the 5th Meeting on U.S. Government Chemical Databases and Open Chemistry hosted by Mark Nicklaus. It was a great meeting. A lot of like minded people and some great work going on to provide access to chemical databases. I’ll blog more when I get back from the ACS Denver meeting this coming week. For now I am simply putting up a copy of the talk I gave.

“ChemSpider is a structure centric database hosted by the Royal Society of Chemistry and integrating over 25 million chemical compounds to over 400 internet-based resources including many public domain databases, Wikipedia, chemical vendors, patents, publications and other web-based services. The intention is for ChemSpider to become one of the primary online hubs for chemists to source chemistry related data. During the development of the ChemSpider database we have utilized numerous approaches to standardizing, curating and validating the data supplied to us for hosting and integration. This presentation will provide an overview of our initial development of the ChemSpider database and provide an overview of our present processes and procedures for handling incoming data depositions. We will also discuss how crowdsourcing can help to expand, curate and validate the data on the ChemSpider database.”

 

 
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Posted by on August 27, 2011 in Publications and Presentations

 

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Community Views and Trust in Public Domain Chemistry Resources

Over the past 4 weeks I have been involved with some new and old friends in the world of chemistry to initiate an analysis of “quality” in public chemistry resources. This is work in progress and involves 3 separate groups (lets call them labs) looking at various resources. Here’s s short description of the project.

The questions we are attempting to answer are:

Core question : what is the quality of data online in public chemistry databases? How accurate and unambiguous is the representation of chemical structures and their measured properties in public chemistry databases?

How capable are the present cheminformatics tools of handling the complexities of structure representations – limited to “small” organic molecules
How hard is it to generate a reference set of highly curated, “gold standard” data (chemical structure and activity) for a database of “known drugs”?

We’ve started with the top 200 selling drugs. The three labs had to come to an agreement about which of the top 200 drugs were small molecules (many of the top 200 are monoclonal antibodies or polymers for example). We then had to decide would we deal with mixtures and combination drugs. Just to identify the list of NAMES of drugs we wanted to deal with was iterative and a negotiation.

Then we decided that each lab would work independently, each lab would have at least two members of the lab working on the same problem independently. We would have both intra-lab and inter-lab comparisons. We decided to start on a set of 10 drug names, using the GENERIC name as the name to work from. I started my part of the work just before I had to give a presentation at the EBI last week and was able to gather a lot of the data before the talk.

Starting with a chemical name how to you determine what the “correct” structure for that drug is. Think it’s easy? Try it! Where would you look? How would you confirm? What would the iterative loop look like in order for YOU to assert the chemical structure(s) for the drug “Vytorin”.

For me the process looks something like this. Use a level of “trust and experience” with previously used resources as a starting point and declare “This is the structure of X based on searching on the drug name for X”. Now, cross-reference, iterate, reiterate, find consistencies and collisions in order to come up with a final assertion, a list of consistent structures and the associated sources, and a set of other resources with inconsistent structures and a list of why they differ. Where possible, and if necessary, make edits to change the information (e.g. ChemSpider and Wikipedia). You can see an example of this for Vitamin K in the talk I gave at EBI here. For ten structures I came up with a number of observations for a number of drugs. The screenshot below summarizes some of the results (Click on the image to see the detail).

Represented in the table is the following information, true at the time of the search and may be already out of date

1) A search for thalidomide in ChEBI gives no hits

2) The structures of Zocor and Crestor on Drugbank are incorrect

3) There are no hits for Voglibose and Crestor on Common Chemistry

4) There were 3 incorrect structures on ChemSpider (now edited of course)

5) For most searches on a drug name on PubChem there are MULTIPLE hits and, for the set examined, the correct structure is in the results set. For example, there are 44 structures of Taxol retrieved with the search and the one I assert to be correct is there.

6) There were two incorrect structures on Wikipedia and one drug without an associated structure.

When I started the work I had a “trust” level for a number of the databases. My basic position at that time was as follows. I could rarely find the correct structure for a drug based on a text-based search of PubChem. I would generally find a set of hits and it was a lot of work to determine what was correct. Common Chemistry was excellent…but limited. Dailymed was generally good but structure representations could be abysmal.  ChEBI, DrugBank, ChemIDPlus and Wikipedia were generally VERY good. Of all of the sources I used, despite the rich data on PubChem, I struggled most with this resource to find the correct structure. The results started to show that my trust perceptions were being challenged.

In parallel with the work to prepare this small dataset for the presentation at EBI I decided that it was appropriate to ask the community for their views on some of the databases I was looking at in this work…specifically asking for how much they “trusted” a resource. Trust means different things to different people. The word, and the question I was asking in the survey, would be interpreted in different ways. But that’s the way we work…so why fight it? The survey is online here…and if you haven’t filled it in PLEASE DO!

The answers to date, from the 46 responders, are below (Click on the image to see the detail):

There are some very interesting results in here…and, I willingly admit, some I find VERY surprising. 1 person has no experience with Wikipedia? Wow. The majority of people have not heard of PDSP, ChemIDPLus, DailyMed or DrugBank…without knowing who the people are that are providing feedback of course I should not be shocked. Most of these resources are not for chemists per se but for Life Scientists. The number of votes for “Always Trust” for ChemSpider and PubChem are very high, and one might say, are a compliment. The results are clearly ChemSpider-biased since I asked the question to my social network. The difference between the people who Always Trust PubChem and Commonly Trust PubChem is one person only. This is wildly different from my own views. I have heard people say that PubChem is the equivalent of quality to CAS except it’s free. Sorry folks…afraid not! (I have since heard at the EBI meeting from one of the people from PubChem that it is possible to do searches in certain ways to limit hits. It should be noted that this does not guarantee that the correct structure is retrieved.) On the flip side to this the distribution of people rarely trusting PubChem is also quite high so someone has had some interesting experiences!

There are a small number of people who NEVER Trust the resources, and early on one person declared they trusted none of them. I trusted myself to tell a colleague…that will be “Egon Willighagen” and this was later confirmed in his blog “Trust has No Place in Science“. That may be true, and the topic of a separate post, but my judgment is pretty good!

How would I fill in the questionnaire. I would NEVER flag “Always Trust” for any of the databases. I would be able to rank order the databases in terms of my perceptions/experience and extracted trust for the quality of results I would find. The answers WOULD be different before I had conducted the work on the first 10 drugs compared with now, after the pre-work.

As the host of ChemSpider I would prefer that no one “Always Trusts” the resource as that will stop people from taking care with the data and thereby removing the possible value of them curating the data. However I am more than happy to have it Commonly Trusted and we have been working hard to gain the community’s trust in this area.

This work has triggered a number of responses….I’ll make my own comments on their positions separately… but their opinions are worth reading:

Egon Willighagen: Truth has no place in Science

Egon Willighagen: Truth has no place in Science Part 2

Christina Pikas: The role of trust in science Christina has a comment “I think that Anthony (sp.) could have chosen a better word than trust in his survey. “which of these have you evaluated and decided you could use? which of these would you prefer to use based on your evaluations of their merit?” Christina is right..I could have chosen a different word but I judge (chosen carefully!) that the responses would not have differed much.

There is also a healthy exchange happening on Friendfeed.

This work has only just started. An examination of >150 “small molecule drugs” by three labs is going to provide a lot of data. The work isn’t over and we have much to do. We’re learning a lot in the process about assertional loops, iterative process, collaboration and agreement. It’s a great adventure.

 
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Posted by on December 11, 2010 in Community Building, Data Quality

 

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Finding the Structure of Vitamin K1 Online

You would think that finding the correct structure of Vitamin K1 online in public domain resources would be an easy exercise. But not so fast. Using the assertion that the chemical structure is correct in the Merck Index, and then wandering through CAS’s Common Chemistry to validate this assumption, this short movie takes us through Wikipedia, Wolfram Alpha, KEGG, DrugBank, PubChem and other online resources to show how complex and impure the public domain databases are in terms of resourcing good quality name-structure associations for chemicals. Vitamin K1 is actually a rather simple chemical structure. Finding the correct chemical structure online…not so simple.

 

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Continuing Conflicts in the Messy World of Internet Chemistry

I have been looking at the state of curated data on the internet and blogged last night about the messy world of curated data. I should emphasize…none of these commentaries are meant to be harsh. Believe me, I’ve gone through the process of validating data and it’s difficult. There will be mistakes but what we need are processes and systems to clean these data up efficiently. If I see an error I want to annotate it and let people know there is an error. With todays’s technologies it is not difficult.

Let’s take another example from DrugBank

That listed chemical name above the structure doesn’t look very consistent…I don’t see any stereochemistry, certainly no “dihydroxy” and overall…yes, it’s definitely wrong. The actual structure for that name is shown below. Looks like an entire half of the molecule is missing. The InChI and InChIKey are for the molecule shown in DrugBank but the link to KEGG is to the molecule shown below…here.

The links on DrugBank to PubCHem and ChEBI are to the molecule to the left. All of the data in the DrugBank record in terms of outlinks  are for the structure on the left EXCEPT the actual structure on the record, and its associated SMILEs and InChIs are for the  “2-amino-3,5-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one” moiety. Oops.

Recently I pointed out to David Wishart, host of DrugBank, some of the issues I had been seeing and it appears there will be a major update to DrugBank in the next few weeks that, in theory, will address some, and hopefully all of these observations.

 
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Posted by on August 16, 2010 in Uncategorized

 

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The Messy World of Even Curated Chemistry on the Internet

Recently I have been spending my night hours looking into the nature of curated chemistry on the internet. 3 years ago I made some assumptions around the quality of certain online datasets when they were deposited onto ChemSpider. It was clear that a lot of internet chemistry datasets were “impure”…I think messy, untrustworthy and confused would be a fairer statement! However, there were a number of datasets that were manually curated and, at initial viewing, were higher quality. With time however I have become increasingly concerned with some of the datasets that I had originally cited as high quality. Over the next few days/weeks I will examine some of these in detail and highlight some of the issues I am seeing. I want to clarify that all chemical compounds, in terms of  their connection tables, their stereochemistry and the association between the compound and the name(s) are assertions. However, there are “norms” for these structures….we would expect a particular structure for aspirin (acetylsalicylic acid ), a single structure for Cholesterol and a single structure for Taxol. By the way, the links to Wikipedia are not assertions that the structures that are presently on Wikipedia are correct representations…but I can confirm that PREVIOUSLY I did work to confirm that every one of these was consistent with my investigations to assert the association between the chemical name and the structure. SInce then it is possible that someone edited the structure…such is the world of Wikipedia!

Two of the linked data sources I have been investigating of late are DrugBank and the Protein Databank. Both of these are manually curated and are expected to be of high quality. In my discussions with various members of the Life Science industry I have heard many positive comments of these data sources as being trustworthy and high quality. I recently downloaded the drugbank small molecule set and started looking at it. Let’s take one example…

The Drugbank record DB02309 has the chemical name “5-Monophosphate-9-Beta-D-Ribofuranosyl Xanthine“. The structure on Drugbank is shown below.

The chemical name above is inconsistent with the structure…there is no stereochemistry in the molecule displayed despite the “-D-” in the name. The IUPAC name listed in the Drugbank record is “[(2R,3S,4R,5R)-5-(2,6-dioxo-3,7-dihydropurin-9-ium-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate” and this clearly does not agree with the displayed structure.

The InChI listed on the record does not include a stereo layer (InChI=1/C10H13N4O9P/c15-5-3(1-22-24(19,20)21)23-9(6(5)16)14-2-11-4-7(14)12-10(18)13-8(4)17/h2-3,5-6,9,15-16H,1H2,(H2,19,20,21)(H2,12,13,17,18)/p+1/fC10H14N4O9P/h11-13,19-20H/q+1). The InChIKey is listed as:

DCTLYFZHFGENCW-NIVOTTSGCB

The Drugbank record links to a structure with full explicit stereochemistry on PubChem here and to the ligand on the PDB ligand database hosted by ChEBI here.

The molfile downloaded from DrugBank has no stereochemistry but lists both Canonical and Isomeric SMILES

Isomeric SMILES O[C@H]1[C@H](COP(O)(O)=O)O[C@H]([C@@H]1O)N1C=[NH+]C2=C1NC(=O)NC2=O
Canonical SMILES OC1C(COP(O)(O)=O)OC(C1O)N1C=[NH+]C2=C1NC(=O)NC2=O

It is clear what has happened, I believe….the Drugbank record has used the canonical SMILES to generate the structure image and has neglected the stereochemistry. However, the names carry the original stereochemistry information while the InChI comes from the structure with no stereo. I think that’s what happened.Let’s confirm.

ASSUMING that the isomeric SMILES string is the appropriate stereochemistry I can convert it and get the following InChIKey (generated using ACD/ChemSketch) and using ACD/Name get the name below). I trust ChemSketch and ACD/Name products to generate both appropriately as I managed these products while at ACD/Labs for over a decade.

DCTLYFZHFGENCW-NSVMUQOTBF

9-{(2R,3R,4R,5S)-3,4-dihydroxy-5-[(phosphonooxy)methyl]tetrahydrofuran-2-yl}-2,6-dioxo-2,3,6,9-tetrahydro-1H-purin-7-ium

On Drugbank the chemical name listed is:

[(2R,3S,4R,5R)-5-(2,6-dioxo-3,7-dihydropurin-9-ium-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate

Okay…the names are subtly different….but there are 3R and 1S centers in each name but they differ, assuming that the nomenclature programs are using consistent numbering schemes. See below.

Name generated from Isomeric SMILES on DrugBank: 2R,3R,4R,5S

Chemical Name on DrugBank: 2R,3S,4R,5R

More on this later. Looking at the linked PubChem record gives the following name: [(2R,3S,4R,5R)-5-(2,6-dioxo-3,7-dihydropurin-9-ium-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate, exactly the same one as listed on Drugbank….so one assumes that the chemical names on DrugBank come from PubChem. Downloading the molfile from PubChem into the same software used to generate InChIs and chemical names gives:

XHDARDSMKMUDDI-XWTUZWARBP

9-{(2R,3R,4S,5R)-3,4-dihydroxy-5-[(phosphonooxy)methyl]tetrahydrofuran-2-yl}-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-9-ium

DrugBank is linked out to the PDB ligands hosted by ChEBI and looking at the XMP ligand here we see:

[(2R,3S,4R,5R)-5-(2,6-dioxo-3H-purin-7-ium-9-yl)-3,4-dihydroxy-oxolan-2-yl]methyl dihydrogen phosphate

This is the SAME stereochemistry in the chemical name as on DrugBank, but actually a different chemical name. It is definitely possible, and common, for different systematic names to exist for the same chemical but it does indicate the challenges of linking based on different identifiers.

DrugBank:

[(2R,3S,4R,5R)-5-(2,6-dioxo-3H-purin-7-ium-9-yl)-3,4-dihydroxy-oxolan-2-yl]methyl dihydrogen phosphate

PDBeChem: [(2R,3S,4R,5R)-5-(2,6-dioxo-3,7-dihydropurin-9-ium-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate

The InChIKeys between the different databases/tools are:

PDBeChem: DCTLYFZHFGENCW-KWDNBKPHDV

DrugBank: DCTLYFZHFGENCW-NIVOTTSGCB

PubChem: XHDARDSMKMUDDI-UUOKFMHZSA-O (this is a StdInChIKey)

ChemSketch: DCTLYFZHFGENCW-NSVMUQOTBF

ALL four are inconsistent.

If I convert the SMILES string listed on the PDBeChem ligand database using ACD/ChemSketch then

O[C@H]1[C@@H](O)[C@@H](O[C@@H]1CO[P](O)(O)=O)n2c[nH+]c3C(=O)NC(=O)Nc23

produces a structure with stereochemistry of 2R,3R,4S,5R and the InChIKey : DCTLYFZHFGENCW-XWTUZWARBW.

The stereochemistry on PDBeChem agrees with that on PubChem (based on the name), the connectivity part of the InChIKey is consistent with all other systems (except PubChem) but is different to all other InChIKeys. It is also possible to download “ideal” and “representative” molfiles from the PDBeChem database.

The InChIKeys between the different databases/tools are now:

PDBeChem: DCTLYFZHFGENCW-KWDNBKPHDV

DrugBank: DCTLYFZHFGENCW-NIVOTTSGCB

PubChem: XHDARDSMKMUDDI-UUOKFMHZSA-O (this is a StdInChIKey)

ChemSketch: DCTLYFZHFGENCW-NSVMUQOTBF

PDBeChem: DCTLYFZHFGENCW-XWTUZWARBW (from Isomeric SMILES converted via ChemSketch)

PDBeCHem: DCTLYFZHFGENCW-RDKRKOOMBN (from molfile from PDBeChem, (2R,3R,4S,5R)

DrugBank also links to the Protein Databank here. XMP is listed as a ligand as shown.

The XMP ligand links here to the detailed page containing the information linked below.

Name XANTHOSINE-5′-MONOPHOSPHATE
5′-xanthylic acid
[(2R,3S,4R,5R)-5-(2,6-dioxo-3H-purin-7-ium-9-yl)-3,4-dihydroxy-oxolan-2-yl]methyl dihydrogen phosphate
Synonyms 5-MONOPHOSPHATE-9-BETA-D-RIBOFURANOSYL XANTHINE
Formula C10 H14 N4 O9 P
Molecular Weight 365.21 g/mol
Type NON-POLYMER
Isomeric SMILES (OpenEye) c1[nH+]c2c(n1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(O)O)O)O)NC(=O)NC2=O
InChI InChI=1/C10H13N4O9P/c15-5-3(1-22-24(19,20)21)23-9(6(5)16)14-2-11-4-7(14)12-10(18)13-8(4)17/h2-3,5-6,9,15-16H,1H2,(H2,19,20,21)(H2,12,13,17,18)/p+1/t3-,5-,6-,9-/m1/s1/fC10H14N4O9P/h11-13,19-20H/q+1
InChI key DCTLYFZHFGENCW-KWDNBKPHDV

The InChIKeys between the different databases/tools are now:

PDBeChem: DCTLYFZHFGENCW-KWDNBKPHDV

DrugBank: DCTLYFZHFGENCW-NIVOTTSGCB

PubChem: XHDARDSMKMUDDI-UUOKFMHZSA-O (this is a StdInChIKey)

ChemSketch: DCTLYFZHFGENCW-NSVMUQOTBF

PDBeCHem: DCTLYFZHFGENCW-RDKRKOOMBN (from molfile from PDBeChem)

PDB_ligand: DCTLYFZHFGENCW-KWDNBKPHDV

Aagghhhhh…InChIKeys get very convoluted! What we see is that the chemical structure on PDB and on PDBeChem are the same. This is good news at least! There is a difference in the InChIKeys when I download the molfile but this can be explained easily…and in a later blog post.

We believe that the structure on PDB should be expected to be correct. We will assert this.

We expect that DrugBank is sourcing the chemical from PDB to add to their database. The chemical structure on DrugBank should coincide with that from PDB. Unfortunately the SMILES on PDB and DrugBank differ in two stereocenters. We don’t know why. Why the inconsistency? If the DrugBank data aren’t from PDB for the XMP ligand where did they come from?

Did PubChem pick up the structure of XMP from the PDB Database or from DrugBank? Let’s see. If I download the 2D molfile from PubChem and generate the chemical name and InChIs I get consistency…PubChem IS consistent with PDB. It is NOT consistent with DrugBank despite the fact that DrugBank is linked into this PubChem record.

This is a very convoluted, and maybe confusing analysis of ONE compound on DrugBank. I have looked at dozens and see similar issues. Assuming that PDB is the source database for data on DrugBank why are the structures differing so much? There are worse examples to come…the linking together of data on the web between even curated databases is an incredible mess.

Caveat: This is detailed and challenging work. I recommend anyone to check my work and see if I missed anything and confirm or challenge the observations as some of the issues I am seeing can be tool-based…the software tools I use may have issues with SMILEs conversion, molfile or SDF reading etc. It is exacting to check chemical structures…

 
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Posted by on August 15, 2010 in Open Science..all its forms, Software

 

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