Philosophy to Chemistry to Elucidation

Ten Years on a Global CASE Project

For the past decade, I had the privilege to be involved in a global project aimed at elucidating unknowns from a variety of clients. The purpose of this project was to explore and expand the utility of a Computer-Assisted Structure Elucidation (CASE) software. It is because of this project that the idea for the blog P2C2E was conceived.

It gives me great pleasure to report that the findings for this project are available online for free in the Journal of Cheminfomatics 2012, 4:5 entitled Blind trials of a Computer-Assisted Structure Elucidation software at http://www.jcheminf.com/content/4/1/5/abstract. The Journal of Cheminformatics is an open access journal publishing original peer-reviewed research in all aspects of cheminformatics and molecular modelling.

 

I would also like to acknowledge the research contributions of my colleagues, Mikhail, Tony, Kirill and Joe, who have helped to make the publication possible.

Mikhail, Tony and Kirill have also released an extensive book on the subject of structure elucidation entitled Contemporary Computer-Assisted Approaches to Molecular Structure Elucidation.

Logic Puzzle #20: Which CH2 will split? … Solution

Diastereotopic protons that are also anisochronous exhibit different chemical shifts. As a general rule, the proximity of a chiral centre will influence the likelihood of diastereotopic proton signals being anisochronous.

For the structure below, the CH2 labeled A is most likely to be anisochronous due to the adjacent chiral carbon.

IUPAC: methyl 7-hydroxy-3,5-dioxo-7-phenylheptanoate

InChi Key: FOGURBALCWIVHU-UHFFFAOYSA-N

A thanks goes to Carlos for submitting a comment.

Logic Puzzle #20: Which CH2 will split?

Diastereotopic protons that are also anisochronous exhibit different chemical shifts. The purpose of this puzzle is to understand a general trend for CH2 groups.

If the following structure, shown below, were dissolved in CDCl3 and a 1H NMR spectrum were acquired on a 500 MHz instrument, which of the following three CH2's would most likely be anisochronous?

IUPAC: methyl 7-hydroxy-3,5-dioxo-7-phenylheptanoate

InChi Key: FOGURBALCWIVHU-UHFFFAOYSA-N

Will the Real Ring System Please Stand Up?

Based on experience, fused ring systems on an unknown structure tend to conjure up variations of odd connections. The possibilities can seem endless.

The diagram, shown below, samples a subset of fused ring systems for a given dataset. It is important to note that although certain systems may be more appealing to the eye, it is imperative for an elucidator to evaluate each variation prior to accepting or rejecting the proposed candidate.

The Stages behind Developing a New Drug in Industry … Part 4

Drug Trials commence with in vitro and in vivo experiments on nonhuman subjects and observing the effects of the candidate drug(s). These are commonly referred to as the pre-clinical trials. Once safe and effective thresholds have been set, the candidate drug(s) can be administered to human subjects and thus begin the clinical trials. The clinical trials are divided into various Phases I, II, III, IV.

In a concerted effort, preformulation studies look at the candidate’s solubility, stability, crystal properties, etc. to optimize the method of delivery. As testing nears completion (or soon after the Drug Design stage is complete), an application for a new drug is submitted to an internal regulatory board and a patent is filed.

The Stages behind Developing a New Drug in Industry … Part 3

The main focus surrounding the Drug Design stage (see diagram in Part 1) is to optimize the hit compound(s) and produce analogues that will increase the activity at the target site. Lead optimization is accomplished through minor modifications of the hit compound.

In Drug Design, medicinal chemists aim to build a diverse library of compounds using the hit compound(s) as a blue print for synthesis. On the flip side, an increase in the compound’s toxicity can have it rejected from the library. For this purpose, many pharmaceutical companies apply at this stage an early ADME/Tox (Absorption, Distribution, Metabolism, Elimination/Excretion and Toxicity) screening.

The Stages behind Developing a New Drug in Industry … Part 2

Following the diagram presented in Part 1, the Drug Discovery stage begins with the identification of a target site that is linked to a disease. (Note: some researchers refer to this as the pre-Drug Discovery stage.)

The main goal behind the Drug Discovery stage is to identify or envision a hit compound(s) that can offer some potential for activity at the target site. A hit compound(s) is uncovered from an array of resources such as: natural products, de novo, high-throughput screening, biotechnology, serendipity, searching across structural libraries, past experiences on similar targets, etc. The hit compound(s) is validated, and barring any toxicity issues, the compound is transitioned from hit to lead compound for the next stage of the development process Drug Design.

The Innovation website presents a similar description on drug development in industry. It also includes a nice movie summarizing the development.

The Stages behind Developing a New Drug in Industry

Many new medicinal drugs produced by pharmaceutical companies follow a very similar pathway starting from the inception of the project idea and ending at the shelves of a pharmacy. Each stage in the development of the drug involves various types of chemists, each lending their expertise at synthesizing, extracting, analyzing and testing the new drug.

The following diagram presents a simplified summary in the development of a medicinal drug. The general stages are 1. Drug Discovery, 2. Drug Design, 3. Drug Trials and 4. Drug Manufacturing/Process.

 

 Please note that this overview may not apply to all cases.

Teaching and Learning by Spectral Example ... Part 1

There are many ways to teach the process of elucidating unknown structures. Offering a student a visual guide, such as seeing firsthand a spectral dataset, can enhance the learning process and better equip the student on future work.

Presented below is a typical elucidation question from a university test. The numerical values have been extracted from a 1H NMR spectrum and the student is basically left to focus on elucidating the unknown.

If a 1H NMR spectrum is presented with the question, as shown below, the student is faced with the tasks of interpreting the spectrum and elucidating the unknown.

Although both approaches can serve a purpose, the latter approach enhances the experience of learning how to elucidate an unknown.

Verifying, Confirming, Making Sure ... Part 1

After a long and arduous attempt at an elucidation, it is quite common to be left with more than one candidate structure. In some cases collecting more data is not an option and an exhaustive database/literature search turns up nothing useful, the alternative approach is to synthesize the proposed candidates and then compare the spectral data to the original unknown.

The example below shows three proposed candidate structure differing in the attachment of the hexopyranoside group. The high degree of similarity between the candidates and the high number of quaternary carbons (11 per structure) makes it very difficult to narrow the list to one candidate.

When data is limited and thus cannot assist in eliminating two out of the three candidates, then the only option left is to synthesize the candidates and compare the spectral data.