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. 

How do Medicinal and Synthetic Chemists use NMR Software?- Part 6

This is a continuation of a series of posts that began here.

In the previous post of this series, I discussed how chemists can extract multiplet reports in journal format on the fly using the same procedure to re-cut integrals in the spectrum. Well in addition to having this nice reporting tool, the software can make valuable use out of this multiplicity information.

The software has the ability to assist the chemist with the interpretation of their spectrum. It does this by using the NMR prediction algorithms embedded in the software. With the use of these algorithms structure interpretation and verification can be employed.

Essentially when a chemical structure is attached to a spectrum, the software will predict a spectrum in the background and automatically compare the predicted spectrum to the experimental spectrum. To do this automatic evaluation, the software will compare three properties between the spectra:

1) Chemical Shift
2) Integration
3) Multiplicity information

As a result, by re-cutting your integrals in the software (and hence defining multiplet patterns and coupling constants) the software will use this information to help a chemist interpret their spectrum. Specifically, it will use this information to provide the chemist with immediate feedback as to what atoms in the chemical structure a multiplet is consistent with. See the movie below:

How do Medicinal and Synthetic Chemists use NMR Software?- Part 5

This is a continuation of a series of posts that began here.

In my last post, I promised to address how, by simply spending 2 minutes re-cutting their integrals, a chemist can extract much more valuable information from their spectra.

The #1 thing in our NMR software that blows chemists away is the production of the following:

¹H NMR (DMSO-d6) Shift d: 7.90 - 7.95 (m, 2H), 7.79 (s, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.33 (dd, J = 8.6, 1.8 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 4.21 (q, J = 7.1 Hz, 2H), 2.53 (s, 1H), 1.25 (t, J = 7.0 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H)

To elucidate and format this information for experimental sections in patents, reports, and publications, this is a very time consuming process by hand.

Can software make it easier?

This capability has been available in our software for a long time. However, in older versions of our software, while it was much easier than doing it by hand, it was a little time-consuming and not obvious how to do this. For example you would have to first pick your peaks in peak picking mode, then you would have to integrate those peaks in integration mode, and finally you would enter Multiplet Mode and create those multiplets. 

As I've already mentioned, Chemists like to re-cut their integrals to make them look nice and normalized. Well now, when chemists do this procedure they are also peak picking and defining multiplet patterns and extracting coupling constant on the fly. Below is an 11 second video clip showing this capability in action. 

Prior to the implementation of this feature, using our software to create these reports was something that was done around patent-writing time. If a patent was being written and experimental sections were needed, the chemist would go back to find their old spectra, and create these reports then.

Now that this process is so quick, easy, and intuitive, I've talked to many chemists around the world who are creating multiplet reports for virtually every spectrum they acquire. They can then paste their multiplet information in a report or ELN, and it will save them time in the patent writing process down the road. And that's not the only benefit chemists can potentially get from extracting this information each time they acquire a spectrum. I'll talk about another, next time.

I wish all the Moms out there a Happy Mother's Day!

How do Medicinal and Synthetic Chemists use NMR Software?- Part 4

This is a continuation of a series of posts that began here.

Here's a short and sweet one.

In my last post, I talked about how having immediate access to the processed data is something that most chemists like. From there, for a lot of chemists the workflow is very simple. Let's just get the integrals looking nice.  Note: They don't generally look nice from automated processing off the instrument unless multiplets are really well resolved and separated.

So for some chemists, re-cutting their integrals and then printing off the spectrum, just might be the peak of their use of an NMR software package.

But what if this very simple process that generally takes no more than 2 minutes could also provide the chemist with much more valuable information about their spectrum beyond integrals?

I'll address that on my next post. 

How do Medicinal and Synthetic Chemists use NMR Software?- Part 3

This is a continuation of a series of posts that began here.

I learned an interesting lesson a few years ago when I was presenting our software on-site to a group of chemists. I began the demonstration by opening up an FID. The response from most of the room was a mix of confusion as well as horror! What is that squigly line you have up on the screen?

It was then I learned that most chemists don't need fancy processing, nor go through the manual steps of FT, baseline correction, phasing, etc. Provided that the sample was prepared and acquired well, the chemist generally doesn't need to do anything fancy to make their ¹H NMR spectrum look reasonable.

This is why in many open access environments that I have visited, chemists are not required to process their data at all. No need to FT their data, nor baseline correct it, nor phase it.

This can be accomplished in a couple of different ways.

You can supply the chemists with processed data from the instrument. In Bruker-speak that's the 1r file. In Varian-speak, it's a phasefile. This is really useful for a chemist because it saves them the additional mouse-clicks for processing data every single time. The only drawback of this approach is that the integrals are usually not all that nice. So a standard workflow for this, is deleting the integrals and re-cutting them a small price to pay, in my opinion.  And of course there are always going to be some cases where the phasing is off, or the spectrum will need some additional baseline correction.

Some other ways, for example, in our software, is to use macros to automatically process the data with one button click. Essentially, you need only create a macro with all the steps set to your liking. Once complete, you can use this macro on all your data. Simply import the FID and click the button. Of course you can also import processed Bruker or Varian files and work with them straightaway in the software. Finally, one of the things we added in the software back in version 10 was Shortcut Mode. With this mode, when you import or drop an FID into the software, it will auto-execute a set of pre-defined processing steps. For example FT, phasing, baseline correction, weighting functions, etc.

All in all, there are a variety of ways to greatly simplify the software interaction for a chemist. I recommend if you are a chemist, or the NMR person responsible for setting up the instrument, that you investigate the possibility of getting direct access to processed data. From there, it's just a matter of cutting integrals, and you're away!

How do Medicinal and Synthetic Chemists Use NMR Software?- Part 2

This is the continuation of a series of posts that began here.

Have you ever worked in an environment where there was a walk-up NMR lab?

If yes, were you fortunate enough to have software in your office or lab where you could view, process, and print out your own plots at your convenience?

If no, then you can relate to having to walk down to the NMR lab to get your print-out only to realize that all you really need is a zoomed in plot from 6.4 ppm -7.3 ppm. Or the processing done off the instrument didn't do the integrals the way you like them.

But John the Chemist, is ahead of you in the queue at the only workstation that has NMR software that allows you to do this. So you have to wait around until he's done his analysis, and he just happens to be one of those chemists who loves to use all the bells and whistles in the software :) Did I mention it was 6:30 PM on Friday?

Having software on the computer in your office or lab (or on your laptop) can result in a huge productivity boost. You may not think it, but I have had many NMR people in companies tell me that this where they get most of their ROI from a deployment of software.

The simple fact that chemists don't have to walk down to the lab for every spectrum, or wait in line to use the software, can save a lot of time and grief!

 

How do Medicinal and Synthetic Chemists Use NMR Software?- Part 1

This post will mark the beginning of a series of several posts.

Please note that for this particular series I am talking mostly about medicinal or synthetic chemists who acquire their own NMR data in an open access environment.

Many chemists in the industry use our software, and when we were doing market research and testing to try and develop the best tool for chemists, I came away with several generalizations. I will post these over the next couple of weeks.

I am going to start off this series by talking about what chemists generally DON'T use NMR Software for.

While there are some chemists who will apply sophisticated processing, accurately integrate, peak pick and characterize all multiplets, assign multiplets in the software to an electronic structure, work with a series, write macros, etc. my observations are that these are few and far between. Most chemists are not going to play with all of the bells and whistles within an NMR software package.

After all, it's not their job to do all of that in most cases. Their job is to make compounds and make sure they made what they thought they made oftentimes using a variety of techniques, not just NMR.

J-Coupler Redux

One of the really nice things that has been available in our software for many years has been the ability to characterize multiplet patterns and coupling constants and to quickly generate a multiplet report like this one:

1H NMR (400 MHz, DMSO-d6)  ppm 0.96 (t, J=7.30 Hz, 3 H) 1.27 (t, J=7.18 Hz, 6 H) 1.41 - 1.54 (m, 2 H) 1.71 - 1.83 (m, 2 H) 3.20 (q, J=7.05 Hz, 4 H) 3.26 - 3.31 (m, 2 H) 3.73 (q, J=6.29 Hz, 2 H) 4.45 (t, J=6.55 Hz, 2 H) 7.20 (s, 1 H) 7.47 (ddd, J=8.31, 7.05, 1.26 Hz, 1 H) 7.70 (ddd, J=8.37, 6.99, 1.51 Hz, 1 H) 7.81 (dd, J=8.31, 0.76 Hz, 1 H) 8.09 (dd, J=8.31, 1.01 Hz, 1 H) 9.12 (t, J=5.67 Hz, 1 H) 10.63 (br. s., 1 H)

Now while the generation of this report in this format is as simply as one button click, characterizing the multiplets can be more labor intensive.

In our software you can characterize a multiplet in one of two ways, automatically, or manually. In the automatic mode, with one button click, you can generate multiplet patterns and coupling constants for all of the multiplets in your spectrum. In the manual way, you can generate the peak picking, integrals, multiplet pattern, and coupling constants, by simply left-clicking and dragging over a multiplet of interest. I prefer the latter method (although a close second is to generate them all automatically and then simply go back and check each individual multiplet for errors).

During the development process of Version 12 of our software, based on customer feedback primarily, we took a look at our multiplet analysis routine, specifically at how a user must interact with the software in the case that the algorithm incorrectly characterized a multiplet (due to missed peaks, severe overlap, significant roofing or tenting, etc.)

Let’s consider an example.  I have a multiplet that the software has incorrectly characterized as a doublet of triplets. Instead I want to make this two overlapping triplets. How would you do it pre- Version 12?:

Now in Version 12:

My hope is that, the method to create 2 triplets is MUCH clearer in Version 12.
To come to the decision of how the New Multiplet Analysis Tool should look, we polled a group of people from different backgrounds: Current users, non-users, expert users of our software, novices, spectroscopists, chemists, students, etc.

We provided an example like this one with 5 different prototypes of the J-Coupler dialog box to see which one was the most clear. The new one we implemented in version 12 was obviously first place by a landslide compared to the others. The implementation from version 11 finished dead last in usability testing.

Here’s hoping that you agree!

If you are interested in future usability testing with our software, please drop me a line.

The Little Things Count

As I mentioned in my last post, with the release of Version 12 out of the door, there are many new and exciting things to explore in our latest release outside of the NMR Workbook.

For me, one of the things that I continue to be amazed about are how much the little things matter to end-users. We spend so much effort and hours to add significant and game-changing functionality like NMRSync, but oftentimes, it is the simplest implementations that make a big difference to the customer's workflow.

Here are a few things that we implemented in Version 12 that have our end-users breathing a sigh of relief:

1) Zoom undo button

The addition of one button can make a big difference. Due to popular demand, we added a toolbar button for the zoom undo feature. Very useful, specifically when you are peak picking a 2D NMR spectrum.Clicking it, allows you to backtrack your zooming.

2) J-Coupler Pop up

In previous version, every time you created a multiplet in the software, the J-Coupler dialog box would pop up. This was a bit of an annoyance for some people, because the only time you need to launch this box, is when your multiplet was characterized incorrectly by the software. Now, whenever you create a multiplet, you get an enhanced label over the multiplet outlining the chemical shift, multiplet pattern, coupling constants, and integral:

 

If the characterization of the multiplet is incorrect, the user simply needs to click on the label to launch J-Coupler and edit their multiplet.

3) Easily Increase or Decrease Multiplet Ranges

Sometimes a user would like to increase or decrease a range for a multiplet of interest. This is especially useful in the case of overlapping multiplets where one multiplet was created originally instead of several. In previous version, users could adjust this range, but only by typing the range in J-Coupler.

In Version 12, we've added an easier way to quickly adjust this range by simply left-clicking and dragging the borders of the multiplet range:

 

4) Spectral Preview Pane

It is now possible to get a quick preview of other spectra without having to make them active by simply hovering your cursor over the respective tabs.

4) MAP in Shortcut Mode

Multiplet Assignment Preview (MAP) was a feature we released in version 11 that helps provide the end-user with assignment assistance. In version 11, when a user entered assignment mode, the software would run a calculation in the background comparing the predicted chemical shift, integration, and multiplicity information with the properties from the experimental spectrum in question. With this information, the software can then suggest the best possible assignments for distinct multiplets in an experimental ¹H NMR spectrum. Unfortunately, this feature went largely undiscovered for many users because it was hidden in assignment mode.

In verison 12, this calculation is automatically run when a structure is attached to a spectrum, and the MAP will appear on the structure as soon as multiplets are created in Shortcut Mode:

From here, the user can quickly assign their multiplets with the aid of the Multiplet Assignment Preview.