Tuesday, February 28, 2017

Biotechnology and drug-design: My latest paper explained without the jargon

Our latest paper has just appeared in the open access journal Chemical Science. It's ultimately related to biotechnology and drug design so first some background.

Most biotechnology and medicine involves proteins in some way. Many diseases involve mutations that alter the function of proteins, most drugs are molecules that bind to proteins and inhibit their actions, and a large part of industrial biotechnology involves making new types of proteins such as enzymes. Like with everything else, it is easier to deal with proteins of you know what they look like but protein structure determination can be very difficult and we don't know what many important proteins actually look like.

The most popular way of determining protein structure is a technique called x-ray crystallography where you basically take an x-ray of a crystal made from the protein. Unfortunately, it can be very difficult or impossible to grow crystals of some proteins and if you can't get the protein to crystallise you can't use x-ray crystallography to find the structure.  The other main way for determining protein structure is a technique called NMR spectroscopy where you basically take an MRI of a solution containing the protein. The advantage is that there is no need for crystallisation, but the disadvantage it that it is difficult to extract enough information from the "NMR-MRI" go get a good structure.

The "NMR-MRI" of a protein actually provides a unique fingerprint of each protein so in principle all one has to do is generate a lot of possible structures of a protein, compute the NMR fingerprint for each, and compare to the measured fingerprint. The structure with the best fingerprint match should be the correct protein structure.  The questions are how to best generate the structure and how to best predict the NMR fingerprint using the structure.

The New Study
In 2015 we published a new method for predicting NMR fingerprints and in the paper that just got published we combined it with a method for generating a lot of protein structures. We started with known x-ray structures and generated millions of relatively small variations of the structure and found the structure with the best match.  We started from a known structure to answer the question: what is the best match we can hope for? The answer is: not perfect but good enough.  Now that we know this the next step will be to start with a structure we know is wrong and see if the program can find the right structure.  Also, our NMR fingerprint method does not generate fingerprints for all parts of the protein so we need to improve the model as well.

This work is licensed under a Creative Commons Attribution 4.0

Monday, February 13, 2017

What are the most important reactions in drug synthesis and stability?

This is a rough draft that I hope to flesh out based on feedback, i.e. "I'm asking, not telling". Please leave a comment or tweet me

1. Aromatic electrophilic substitution of heteroaromatics
2. Suzuki coupling of heteroaryl halides
3. Diels-Alder reaction (of what)?
4. Michael reaction (of what)?
5. Friedel-Crafts alkylation (of what)?
6. Nazarov cyclization reaction (of what)?
7. ...

Stability (Probably solvolysis and oxidative degradation, but can we be more specific)
1. Autooxidation of C-H bonds?
2. Ester hydrolysis?
3. ..

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Sunday, February 5, 2017

Preprints and the speed of publishing

When I talk about preprints with colleagues some of them say "Oh, what's the rush?" or "Publishing is so fast these days. Why, my last paper was online 6 weeks after submission don't you know" and then go on to clean their pipe with a thoughtful smile or get up to stoke the coal fire.

I'm currently writing a couple of proposals and as I was updating the reference list on one of them when I noticed that two preprints I cited apparently still haven't been "published" by a journal.  One of them first appeared on arXiv on October 7th and the other October 27th.

Both papers are important to the proposal in the sense that they changed my thinking on what is possible and I think the proposal would be less ambitious if I hadn't read them. So I am very happy these authors chose to deposit them as preprints.  I wish more people would do this and I wish fewer journals/journal editors would stand in the way of them doing so.

This work is licensed under a Creative Commons Attribution 4.0