Ryan's Blog on NMR Software

From FID to Structure in 30 Minutes? Investigating the CASE Limiting Step

In yesterday's post I pointed you to an article that has become the most accessed article of all time in the Journal of Cheminformatics, co-authored by representatives of ACD/Labs.

This article is a very comprehensive outline of the different approaches, developments, and successes of the development of CASE (Computer-Assisted Structure Elucidation) systems . I hope you agree that this technology has come a very, very, very long way, to the point that there are many spectroscopists around the world using ACD/Structure Elucidator routinely to identify unknowns in thier labs whether they be natural products, impurities, degradants, metabolites, etc. 

Anna Codina from Pfizer is an example of just one of those users. She has been a long-time user of Structure Elucidator, and one of the very best in the world. She, along with her group, has really stretched the limits and applications of the software and has also been instrumental in the ongoing improvement of this software over the years. 

At SMASH 2009, Anna shared some of her most recent experiences with the software in a presentation entitled, "From FID to Structure in 30 minutes?" This presentation can be accessed here.

For this presentation, she wanted to see whether it was possible to do a full elucidation starting from the raw data, all the way to the solution in less than 30 minutes. She was able to achieve this with several of her in-house Pfizer compounds, and then, for the purposes of this presentation reproduced these findings with compounds she could share in a pubic forum.

In this presentation she goes through 3 such examples.

The most interesting piece for me was her discussion regarding the CASE limiting step in slides 9 and 10.

In an ideal world, we would be talking about completely automated structure elucidation. Of course, we are not quite there yet, but it is still a dream, as Elyashberg et. al refer to it in the J. Chem. Inf. article.

In the meantime, the process generally involves some manually handling of the data. For this process the general principle applies, "Garbage IN- Garbage OUT"

So the quality of data as well as the peak picking of said data is crucial.

The peak picking of multiple spectra is what Anna was referring to as the CASE-limiting step. We have made tremendous strides over the years to simplify this process as much as possible (Check out the demonstration movie here). But the traditional argument seems to still apply for some:

Why would I spend so much time peak picking all my 2D spectra?

By the time I finish picking and grooming the data, I have already solved the structure, so what's the point?

I will try to address these questions in a different post, but in the meantime, what's Anna's answer?

NMR Workbook, and specifically the NMRSync technology that we developed and released late last year. Note, that NMR Workbook is included with ACD/Structure Elucidator.

Anna proclaims that thanks to NMR Workbook, there is no longer a CASE-limiting step. With syncrhonized peak picking which carries through peak picking applied in one spectrum, to all others associated with the sample, the time spent to prepare the data is drastically reduced and is more consistent with the natural workflow.

For those unfamiliar with NMR Workbook and the NMRSync functionality, I introduced it on the blog about a year ago:

http://acdlabs.typepad.com/my_weblog/2008/12/if-all-of-these-spectra-are-from-the-same-compound-why-am-i-handling-them-all-separately.html

If you want to skip right to the demonstration go here:

http://www.acdlabs.com/products/spec_lab/exp_spectra/nmrworkbook/movie/NMRWorkbookFlash.htm

This product has turned out to be immensely popular and has evolved a long way in just one short year. Admittedly, it's probably been the biggest reason I have not been blogging as much over the past year, I have been touring the world showcasing this product, as well as our other solutions.

I hope over the next little while I can dive a bit more into the details of the product.

Stay Tuned.

Most Accessed Article on Journal of Cheminformatics of All Time!

An article co-authored by several ACD/Labs scientists, the Russian Academy of Scientists, and ChemZoo, Inc. has been generating a lot of interest over the past year.

In fact, this article entitled, "Computer-assisted methods for molecular structure elucidation: realizing a spectroscopist's dream" is the most accessed article of all time, on the Journal of Cheminformatics website.

The news gets better. This article is FREE for your reading pleasure! As per the policy of the Journal:

"The Journal of Cheminformatics offers scientists the opportunity to publish their research rapidly in an open access medium that is freely available online to researchers worldwide. All manuscripts submitted to the journal are subject to rigorous peer review. Published material may include electronic supplementary material, such as animations (e.g. graphical chemical structures) or data (e.g. spectra) that can be downloaded for a reader's use.

The Journal of Cheminformatics aims to work closely with operators of open data repositories such as PubChem. Requests for collaboration are welcome; please contact the Editorial Office."

This motivation for this article was to mark the 40 year anniversary of published developments regarding CASE (computer assisted structure elucidation systems).

It a very interesting read that draws from many meaningful publications on CASE over the last 40 years and tracks history to outline some of the approaches that have been considered, implemented, and successful.

Some of the more significant developments such as fuzzy generation, used to deal with the ambiguity of 2D NMR experiments, as well as the determination of relative stereochemistry of large and rigid molecules with many stereocenters are discussed in this article.

I could spend more time talking about this article, but as I've already mentioned, it's FREE and can be accessed here:

http://www.jcheminf.com/content/1/1/3

Enjoy and feel free to leave any comments for the authors, and I will be sure to get them. 

Hope to See you at SMASH 2009

If you are attending SMASH in Chamonix next month please make sure to drop by and see my colleagues and I. We'll be happy to show you what is new in the software, and what we are thinking about moving forward.

In addition, on Sunday, Sept. 20th at noon, we will be holding our annual symposium where representatives from ACD/Labs as well as some of our guest speakers from industry and academia will share the latest developments and applications of our software.

We will be discussing primarily our work, and the work of others toward Computer Assisted Structure Elucidation (CASE), Advances in Automated Structure Verification, as well as the progress we've made on our new  ACD/NMR Workbook release.

I am delighted to welcome as guest speakers, Anna Codina from Pfizer Sandwich, Duncan Farrant from GSK, Stevenage, and Craig Butts from Bristol University.

To see the full agenda for our symposium, and to register online, please visit:

http://www.acdlabs.com/um/2009/smash/seminar.html

Please register and join us for a free lunch prior to the symposium.

I realize travel budgets are tight these days, but it's a great conference, a great program, great people, and a wonderful location.

I hope to see you there.

If All of these Spectra are From the Same Compound, Why am I Handling them all Separately?

Last week, we released a new, updated version of 2D NMR Manager, and have decided to call it ACD/NMR Workbook, as the functionality and possibilities within this software package have significantly changed.

Over the last few months I have been touring the world, presenting about this new product and it's new NMRSync functionality. Please see my presentation below to learn why we did it, what it is, and how it works:

Alternatively, I highly recommend you check out the link here, to watch a demonstration of the software in action.I hope you won't be disappointed in what you see.

Lots more exciting new things in Version 12, and I hope to blog about them over the next little while.

SMASH 2008-Session on Computer Aided Structure Structure Identification

Speaking of the CASE review article in Progress in NMR, I thought I would take the opportunity to mention the upcoming session on Computer Aided Structure Identification that will take place at the SMASH 2008 Conference in Santa Fe New Mexico in September.

One of the presenters in the session will be none other than Mikhail E. Elyashberg who has made tremendous contributions to this area. In his presentation he plans to lay out the 40 year history of CASE and I am sure it will be a terrific presentation.

8 years ago Mikhail was one member of a team of 4 who received the State Award of the Russian Federation for their pioneering work into the automated analysis of complex compounds. It is great to see Mikhail continue to work, publish, and present on this topic.

Rich Beger from the National Center for Toxicological Research and Richard Newmark will also be presenting in this session.

Not to mention that Gary Martin (another Co-author of the CASE article in Progress in NMR) is slated to speak in the New Experimental NMR Techniques session.

So there's a number of reasons for you to get away from the lab for a few days in September and attend SMASH 2008.

Looking for a Great Weekend Read?

In fact, to borrow a phrase from a colleague, this might be the defacto article on Computer Assisted Structure Elucidation (CASE) for the next decade!

This article written by Mikhail Elyashberg, Antony Williams, and Gary Martin spans across two issues of the review journal, Progress in Nuclear Magnetic Resonance Spectroscopy. 

This article entitled, entitled, "Computer-Assisted Structure Verification and Elucidation Tools in NMR-based Structure Elucidation" is available online and you can review a preview of the content at:

http://dx.doi.org/10.1016/j.pnmrs.2007.04.003

This is a very important and comprehensive review of modern expert CASE systems over many years. It includes specific examples of complex natural product structures that have been automatically elucidated using such systems.

I thank the authors of this publication for their contributions in this area, and the efforts they have now put forth to communicate this story to the scientific community.

Please obtain a copy for yourself, I can promise that it is a very informational and intriguing read for those of you who do NMR regularly.

New Blog by Arvin Moser

Those of you who are current users may recognize the name Arvin Moser as he has spent many years as both a Technical Support Specialist and Application Scientist at ACD/Labs.

Arvin has decided to start a blog and share his knowledge and experience about structure elucidation. I think this blog promises to be a very interesting one as Arvin has a wealth of experience in both manual and computer assisted structure elucidation (CASE).

From Arvin's About Page:

My goal is to focus on the science of data interpretation and structure elucidation. I would like to pass on my experiences including what I have learnt from the experts. By sharing these experiences with the scientific community, I think an emerging elucidator can be better equipped with handling anything that comes their way.

Visit Arvin's Blog here.

Dereplication? Version 11- Searching PubChem using ACD/Structure Elucidator

This resource will likely only be useful to readers who are currently using ACD/Structure Elucidator, however, I do have two questions for my general audience and I would greatly appreciate your comments.

First things first, a technical note has been created to explain how to install and search the PubChem Database. It can be downloaded here:

http://www.acdlabs.com/download/technotes/110/nmr/pubchem.pdf

You'll notice in the introductory paragraph of this technical note it uses the term "dereplication" to describe the process of searching a spectral database with the NMR data of an "unknown" prior to elucidation.

Can this process REALLY be called Dereplication?

How do you define the term, "dereplication"?

The first hit from Google (not necessarily the most accurate) provides the following definition:

De`rep`li`ca´tion

the process of testing samples of mixtures which are active in a screening process, so as to recognize and eliminate from consideration those active substances already studied; - a stage subsequent to the preliminary screening in the process of discovery of new pharmacologically active substances in mixtures of natural products; - also called countersceening.

I think this is a reasonable definition based on my understanding of the process.

A few years back, I did quite a bit of research talking to some natural products scientists to try and uncover this idea. I got various different views on the topic and the definition of this term and it's applications. A common response that I got was something like:

"If it is an unknown compound, and I am able to use spectral databases to identify known compounds prior to elucidation, I'd call that dereplication"

And there were this valued added comment:

"If I am able to identify known compounds using a NMR search method, and avoid even two repeat elucidations per year, that's incredibly valuable"

Probably the best, and most comprehensive responses I got were:

"Usually dereplication is done as early as possible in the process. If you have already isolated the compound to NMR purity most of the costs have already been incurred. Typically LC-MS and/or LC-UV on an early crude subsample is the most cost effective. However some pharma use LC-NMR, and using this technique is where NMR database searching can reap rewards."

"Dereplication is done on only a small crude sub-sample of the organism/extract long before large-scale isolation by chromatography is performed. Dereplication only makes sense at an early enough stage in natural product discovery to prevent the high cost isolation chemistry from being undertaken. Hence, only early stage dereplication makes business sense. It would be better to classify dereplication based on the hyphenated techniques. Your late-stage dereplication is really known structure matching/identification - a worthwhile and necessarry pursuit as dereplication is NEVER perfect."

"Searching databases by NMR prior to an elucidation represents dereplication in only some laboratory instances. This workflow would work very well in those laboratories that employ employ LC-NMR as a tool for the separation of natural product extracts. A fraction's NMR spectrum can automatically be searched in a database to identify isolates that contain known compounds. However, this type of analysis is not done in all research labs. Therefore, without this type of analysis, the major costs of natural products research are generally incurred prior to NMR analysis. NMR is introduced as an elucidation tool after separation and purification. A combination of LC-MS and LC-UV, for example, can be used effectively for dereplication purposes as MS can provide an accurate mass and structural information and UV can provide insight on existing chromophores and a compound's structure."

It appears that hyphenated techniques are likely the key to dereplication.

Some good work has be done here using LC-UV-MS, for example:

Merck in NJ:

http://www.massspec.com/downloads/ASMS2006_Poster_Zink_TuP313.pdf

http://www.cosmoscience.org/pdfs/Session%20IV_Presentation%20I_Zink.pdf

Microbial Screening Technologies developed an in-house, metabolite recognition software called COMET that compiles and analyses co-metabolite patterns in natural product mixtures:

http://www.microbialscreening.com/

Dereplication using LC-NMR:

http://www3.interscience.wiley.com/cgi-bin/abstract/76509553/ABSTRACT
http://www3.interscience.wiley.com/cgi-bin/abstract/110574737/ABSTRACT

The late, great John Faulkner once said in a Philosophical Basis for Structure Elucidation:

"The problem with using NMR for dereplication is that no reliable method of searching NMR spectral libraries  has yet been devised, although there have some attempts to construct and search ¹³C NMR libraries. It is possible that computers will, in the future will be able to recognize and compare the patterns that are found in NMR spectra but that seems a long way off."

I think that computers can do this now. But what to call it?

Can an NMR DB search be termed dereplication?

Should it be positioned around and to only those people who use LC-NMR?

What do we call the discovery of known compounds by NMR prior to structure elucidation?

Provide your own thoughts on this.

More on Indirect Covariance

Gary Martin has added a comment to an earlier post I wrote on Indirect Covariance and was kind enough to post an updated publication list on this topic. I have simply copy and pasted his comments in this post to provide more exposure to his list:

Ryan, it has been a while since you updated the publication list on indirect covariance methods, so I thought it appropriate to do that with a post:

F. Zhang and R. Bruschweiler, J. Am. Chem. Soc., 126, 13180 (2004).

K. A. Blinov, N. I. Larin, M. P. Kvasha, A. Moser, A. J. Williams, and G. E. Martin, Magn. Reson. Chem., 43, 999 (2005).

K. A. Blinov, N. I. Larin, A. J. Williams, M. Zell, and G. E. Martin, Magn. Reson. Chem., 44, 107 (2006).

K. A. Blinov, N. I. Larin, A. J. Williams, K. A. Mills, and G. E. Martin, J. Heterocyclic Chem., 43, 163 (2006).

K. A. Blinov, A. J. Williams, B. D. Hilton, P. A. Irish, and G. E. Martin, Magn. Reson. Chem., 45 544 (2007).

W. Schoefberger, V. Smrečki, D. Vikić-Topić, and N. Müller, Magn. Reson. Chem., 45, 583 (2007).

G.E. Martin, P. A. Irish, B. D. Hilton, K. A. Blinov, and A. J. Williams, Magn. Reson. Chem., 45, 624 (2007).

G.E. Martin, B.D. Hilton, P.A. Irish, K.A. Blinov, and A.J. Williams, J. Heterocyclic Chem., 44, 1219 (2007).

G.E. Martin, B.D. Hilton, P.A. Irish, K.A. Blinov, and A.J. Williams, J. Nat. Prod., 70, 1393 (2007).

G.E. Martin, P. A. Irish, B. D. Hilton, K. A. Blinov, and A. J. Williams, Magn. Reson. Chem., 45, 883 (2007).

B. Hu, J.-P. Amourex, and J. Trebose, Solid State Nuclear Magnetic Resonance, 31, 163 (2007).

G.E. Martin, B.D. Hilton, P.A. Irish, K.A. Blinov, and A.J. Williams, J. Nat. Prod., 70, 1966 (2007).

D. A. Snyder, Y. Xu, D. Yang, and R. Bruschweiler, J. Am. Chem. Soc., 129, 14126 (2007).

G.E. Martin, B. D. Hilton, K. A. Blinov, and A. J. Williams, Magn. Reson. Chem., 46, 138 (2008).

G.E. Martin, B.D. Hilton, K. A. Blinov, and A. J. Williams, J. Heterocyclic Chem., 45, in press (2008).

This is the list I currently have. Note that this list does not contain additional papers that pertain to homonuclear covariance processing methods. I don't have that list of publications handy that I can cut and paste into this post.

Thanks Gary!

Meet Quindolinocryptotackiene

Tony over at ChemSpider takes us on a trip down memory lane to one of the most successful stories surrounding Computer Assisted Structure Elucidation (CASE).

It is also the best example of achieving symbiosis between a spectroscopist (in this case Gary Martin) and software (ACD/Structure Elucidator) I have ever seen.

He is referring to "Solving a structure computationally after 10 years of human effort" that was presented by Gary and Tony at the ASP Meeting in 2003 (It's a long presentation but skip to slide 44 to get to the meat of the presentation).

There is also a publication on this story. 

Tony's purpose for resurrecting this story is as follows:

Now, we THINK we have it elucidated correctly. However, we would like to confirm it. Synthesis of the molecule in question, further NMR data generation and a crystal structure would help finish this work fully. This is a call to organic chemists to participate in a hobby project. Anybody want to help? We guarantee a publication etc. The structure is shown below. Contact me at antonyDOTwilliamsATChemspiderDOTcom. Thanks!

Hopefully someone is willing to step up to the plate.

I'd also like to take this opportunity to, once again, point out that CASE is not simply about piling a bunch of data in a piece of software and getting the answer out the other end. Sure this is possible, but it usually benefits when an experienced spectroscopist works with it and shares their knowledge of the existing chemistry. I think Gary's story is a perfect example of that.

That being said, in Gary's case, along with comments I have received from Dr. Shaun Tennant (another elucidator user) in the past, the software is an unbiased approach that will propose some things that the spectroscopist simply might not think about. Knowledge can sometimes be your enemy.