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Will the correct structure of Fluvastatin please stand up

29 Jul

Eventually there will be simple answers to the question commonly asked by chemists. “What is the chemical structure of INSERT NAME?” This is going to be true for drugs as the various online databases work together to clean up, curate, qualify and declare what a chemical structure is for a particular drug. While we can have the purists argument about structure drawings not representing reality, for example that compounds are atoms bonded together by shared clouds of electrons that at any point in time may be changing, reorganizing, tautomerizing etc the reality is also that we need a common language for information exchange and in the world of visual depictions for chemistry the layout in a 2D structure diagram is it. As we come together as a community to agree on preferred ways to standardize chemicals to assist in representations in databases for example, this situation will improve. The efforts of the FDA to define structure representation standards, with the support of pharma, will contribute. For now we are left with the challenges of different representations in different databases as well as simply the quality of data being fed into these databases. These are some of the issues we are trying to resolve as we build Open PHACTS. We are trying to link data from various resurces, noting and resolving conflicts when we can, and curating as necessary with the ultimate intention that this information will flow out into the community and be picked up by the database hosts and addressed, fixed, challenged as appropriate.

I’ve been looking for a new example showing the challenges of data integration considering that in Open PHACTS at present we are integrating chemistry from three primary data sets (for now)… DrugBank, ChEBI, ChEMBL. So, let’s consider Fluvastatin. The usual challenges of trying to determine what the “correct” chemical structure representation is for the compound is an iterative loop but let’s see what we can find in our datasets as we iterate. I KNOW from 4 years of looking at chemistry on Wikipedia that the data quality for chemical compound representations is very good. So, starting there we find the Wikipedia record here. The DrugBox links to a number of records in other databases.

One of these is ChemSpider and it has the SAME representation. On ChEBI the representation is inconsistent with no defined stereochemistry (except the E- double bond). Since ChEBI is manually curated and the compound carries 3 stars this should be correct. There are two records LINKED from this ChEBI record.

rel-(3R,5R)-fluvastatin (CHEBI:38566)

rel-(3R,5S)-fluvastatin (CHEBI:38561)

On Drugbank the compound has INVERTED stereochemistry from that on ChemSPider and Wikipedia… WP and ChemSpider has 3R,5S while DrugBank has 3S,5R but it DOES say in the pharmacodynamics sectionb “It is prepared as a racemate of two erythro enantiomers of which the 3R,5S enantiomer exerts the pharmacologic effect. ” confirming that the 3R,5S form is the ACTIVE form.

ChEMBL matches Wikipedia and ChemSpider here.

So, to summarize what we get when we search for Fluvastatin

Stereo 3R,5S for Wikipedia, ChemSPider, ChEMBL

Stereo 3S,5R for DrugBank

No stereo for ChEBI

Welcome to the complexities of name-structure relationships. These are some of the challenges we need to deal with on Open PHACTS. Dailymed defines the sodium fluvastatin as “Fluvastatin sodium is sodium (±)-(3R*, 5S*, 6E)-7-[3-(p-fluorophenyl)-1-isopropylindol-2-yl]-3,5-dihydroxy-6-heptanoate” so the relative form….

 

 

 

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.
1 Comment

Posted by on July 29, 2012 in Data Quality, Quality and Content

 

One Response to Will the correct structure of Fluvastatin please stand up

  1. Chris Evelo

    July 30, 2012 at 4:14 am

    Interesting! Since Fluvastatin is a registered drug I would assume there is also a registered structure with information on the stereochemistry involved? Is that information available somewhere? For instance from FDA?

    As a side note. The Wikipedia entry mentions a possible antiviral effect “shown” in 31 patients. I don’t think anything can really be shown in 31 patients, although it could be enough to trigger further research. Should we update that information?

     

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