Reflecting on 20 Years of Computer Assisted Structure Elucidation: What CASE has Achieved and What Lies Ahead

September 12, 2018

by Jessica Litman, Marketing Communications Specialist, ACD/Labs

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Do you ever stop to think about how technology has changed in the last 20 years? I do when I’m watching TV shows or movies that were made in the 90’s or early 2000’s. In a way, it’s sobering to remember that the smartphone I rely on for everything has only been around since 2007. More so, 20 years ago this article might still be loading in Netscape Navigator, running on Windows 95, using dial-up internet. Our expectations of device speed and convenience have drastically changed as technology has rapidly evolved.

At ACD/Labs, we are celebrating the 20^th birthday of ACD/Structure Elucidator, our most powerful computer assisted structure elucidation (CASE) product. Much like a calculator, CASE is a tool for speeding up spectral analysis and verifying the results of de-Novo Structure Elucidation. CASE has made an amazing impact on our ability to elucidate compounds quickly and accurately by NMR, and has helped spectroscopists solve some of the most challenging elucidations. To better understand how CASE will influence research and development in the coming years, let’s look back on how it has evolved throughout these past 20 years with respect to advancements in modern technology.

The Development of CASE

While CASE as a product has been around for 20 years, the concept of CASE was conceived in 1968 by Mikhail Elyashberg and Lev Gribov [1]. They suggested using a computer to find the structure of a compound using IR spectra, which at the time was much more abundant and established than NMR spectroscopy.

Fast forward to 1997 when ACD/Labs released the first version of Structure Elucidator. It was available on CD ROM and only included IR and 1D NMR spectra. It would search through a library of 400,000 fragments and filter by spectrum-structure correlations.
When Apple’s iPod was first released in 2001, Structure Elucidator began to take a more familiar shape. It could use 2D NMR spectra, including HSQC, HMBC and COSY, and the molecular connectivity diagram (MCD) appeared in the program [2]. 

Developmental Highlights

Many of the fundamental aspects of CASE were developed between 2002 and 2009. During this time, CASE’s potential was realized by elucidating previously unsolvable structures. This helped to establish CASE as an integral approach to structure elucidation. Key developmental highlights include:

2002                    

CASE: Following structure elucidation, fast ¹³C NMR prediction and HOSE code simplified choosing the structure that best matched the experimental data [3]

Popular Technology: At the same time, Nokia introduced the (nearly) indestructible 6610, complete with one of the earliest addictive phone videogames, Snake.

2003

CASE: CASE is used to solve the structure of quindolino-cryptotackieine, which had been challenging NMR experts for the preceding 10 years [4].

Popular Technology: Dr. Paul Lauterbur and Sir Peter Mansfield are awarded the Nobel Prize in Medicine for the development of MRI

2004-2005

CASE: Structure Elucidator solves a molecule with 90 skeletal atoms, and a program for determining the relative stereochemistry of an elucidated structure was developed. This program was implemented into Structure Elucidator [5][6].

Popular Technology: The way humans navigate drastically changed when Google Maps was introduced.

2007-2009

CASE: Fuzzy structure generation was introduced in Structure Elucidator. This unique feature allows the correct solutions in the presence of an unknown number of non-standard correlations with unknown lengths in 2D NMR data. Furthermore, algorithms were developed to solve large symmetric molecules from 2D NMR spectra, which historically was a challenge for CASE [7][8].

Popular Technology: Microsoft introduced Windows 7 and Bitcoin was created.

This modern Nokia more closely resembles a computer than a phone

2010 – To the Present Day  

Similar to how mobile phones evolved from being a single purpose device into handheld computers, CASE has evolved into a multi-purpose technique that is not limited to NMR experts. The best example of this is automated verification. In 2010, over 20 natural product structures were revised as a result of CASE [9]. This reinforced the notion that CASE can also be used as a verification tool. In 2013-2014, this point was further established when the structure of a natural product was revised using only CASE – no additional experiments were performed [10]. This application of CASE led to a novel automated verification tool, which was released in 2017, called unbiased verification (UBV) [11]. UBV is unique since it is based on the structure generator used in the ACD/Labs CASE system. The advantage of unbiased verification is that it generates all possible structures that might be compatible with an NMR dataset and determines which one is truly the best match.

While that is a good example, it is not the only example of CASE becoming more broadly applicable. CASE has been paired with DFT chemical shift calculations to achieve a more versatile NMR-based structure elucidation method, and development continues to improve its stereochemistry prediction abilities [12].

CASE has come a long way in 20 years – from being limited to 1D NMR and IR spectra, to a robust elucidation tool that can be applied to a variety of 1D and 2D NMR datasets and any unknown small molecule. In the future, perhaps CASE will become a fully automated technique. I’m curious to how we will look back on today when CASE has been around for 40 years.

For more information on ACD/Structure Elucidator or to speak with one of our NMR spectroscopy experts, please contact us.  

 

References     

1. Elyashberg, M.E., Blinov, K.A., E.R. Martirosian. A New Approach To The Computer-Aided Molecular Structure Elucidation: Expert System STRUCTURE ELUCIDATOR. Laboratory Automation and Information Management, 1999 34, 15-30.
2. Blinov, K.A., Elyashberg, M.E., Molodtsov, S.G., Williams, A.J., Martirosian, E. An expert system for automated structure elucidation utilizing ¹H-¹H , ¹³C-¹H  and ¹⁵N-¹H  2D NMR correlations. Fresenius Journal of Analytical Chemistry, 2001, 369, 709-714.
3. Elyashberg, M., Blinov, K., Williams, A.J., Molodtsov, S., Martirosian, E. Application of a New Expert System for the Structure Elucidation of Natural Products from 1D and 2D NMR Data. J. Nat. Prod., 2002, 65, 693-703.
4. Blinov, K.A., Elyashberg, M.E., Martirosian, E.R., Molodtsov, S.G., Williams, A. J., Sharaf, M. M. H., Schiff, P. L. Jr., Crouch, R.C., Martin, G. E., Hadden, C.E., Guido J.E., Mills, K.A. Quindolinocryptotackieine: the Elucidation of a Novel Indoloquinoline Alkaloid Structure Through the Use of Computer-Assisted Structure Elucidation and 2D NMR. Reson. Chem., 2003, 41, 577-584.
5. Elyashberg, M. E., Blinov, K. A., Molodtsov, S. G, Williams, A. J., Martin, G. E. Structure Elucidator: A Versatile Expert System for Molecular Structure Elucidation from 1D and 2D NMR Data and Molecular Fragments. J. Chem. Inf. Comput. Sci., 2004, 44, 771-792.
6. Smurnyy, Y. D., Elyashberg, M. E., Blinov, K. A., Lefebvre, B., Martin, G. E., Williams, A. J. Computer-aided determination of relative stereochemistry and 3D models of complex organic molecules from 2D NMR spectra. Tetrahedron, 2005, 61(42), 9980-9989.
7. Elyashberg, M. E., Blinov, K. A., Williams, A. J., Molodtsov, S. G., Martin, G. E. Fuzzy Structure Generation: A New Efficient Tool for Computer-Aided Structure Elucidation (CASE). Chem. Inform. Model, 2007, 47, 1053-1066.
8. Elyashberg, M., Blinov, K., Molodtsov, S., Smurnyy, Y., Williams, A., Churanova, T. Computer-Assisted Methods for Molecular Structure Elucidation: Realizing Spectroscopist’s Dream. Journal of Cheminformatics 2009, 1:3 doi:1186/1758-2946-1-3
9. Elyashberg, M., Williams, A., Blinov, K. Structural revisions of natural products by Computer Assisted Structure Elucidation (CASE) Systems. Nat. Prod. Rep., 2010, 27(9), 1296-1328.
10. Elyashberg, M., Blinov, K., Molodtsov, S., Williams, A.J. Structure Revision of Asperjinone Using Computer-Assisted Structure Elucidation Methods. J. Nat. Prod., 2013, 76, 113−116.
11. Argyropoulos, D., Golotvin, S., Litman J., Remove Your Bias During Structure Verification by NMR. ANZMAGazine, 2017, 5, 18-22.
12. Buevich, A.V., Elyashberg, M.E. Towards unbiased and more versatile NMR-based structure elucidation: A powerful combination of CASE algorithms and DFT calculations. Magn. Reson. Chem., 2018, DOI: 10.1002/mrc.4645

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