30 July 2008

Births and Deaths

Everyone knows that Roche made an offer to buy Genentech. What is not as widely know is that, if the deal goes through, Roche will shut down its Palo Alto site, which employs about 1000 people, according to Palo Alto Online.

How does this affect fragments? Hoffmann-LaRoche in Switzerland published an early example of fragment work on DNA gyrase way back in the year 2000 (using a technique called needle screening), and recently Roche Palo Alto has published some very useful guidance on how to identify - and avoid - screening artifacts in SPR (see glossary, 28 July). Practical Fragments wishes the Palo Alto folk the best of luck, and hope they put their considerable skills to good use wherever they land.

On a happier note, the same week the Roche-Genentech deal was announced, newborn Zenobia Therapeutics announced that it had commenced operations. Founded by Vicki Nienaber, who published what I believe is the first demonstration of crystallography-based fragment lead discovery while at Abbott (also in 2000), the company plans to pursue partnerships as well as its own work on neurological and muscular degenerative diseases. The company's motto is "fighting to cure disease, one fragment at a time," and we look forward to watching them grow.

28 July 2008

Glossary v1.0

There has been some requests for a glossary/thesaurus especially for the newbies.

I promise you this is not a complete list, nor will it be necessarily alphabetical.

Abbott: Pharmaceutical company considered to be the pioneers of Fragment-based Drug Discovery
CADD: Computer-aided Drug Design. This is a "design" vs. a "discovery" method.
FBDD: Fragment-based Drug Discovery. An ExecDir I knew preferred Discovery over Design for odd reasons, which in typical fashion I forget here.
FBLD: Fragment-based Ligand Discovery. This actually makes more sense, because we are looking for ligands to targets, which eventually will be turned into to drugs. This is to create more of a contrast to standard HTS (see below) which screens for drugs.
Fragment: A chemical structure smaller than the final drug.
IP: Intellectual Property, as in there is none for fragments (That's for you David.)
ITC: Isothermal Calorimetry. Proof that you really needed to take that thermodynamics course in college, and you probably should have taken one in grad school.
Ligand: Chemical moiety that binds (or mostly doesn't bind to target).
NMR: Nuclear Magnetic Resonance Spectroscopy Method which uses the quantum nature of nuclear spins to generate data on the binding and structure of ligands and target.
SBDD: Structure-based Drug Design. I think this is more acceptable to say "drug design" because of inherent use of CADD. There have been more Nobel Prizes for NMR than X-ray.
SPR: Surface Plasmon Resonance, a.k.a BiaCore. Although this is more Xerox than anything else. The method is SPR, the maker of the machines is BiaCore, now a wholly owned subsidiary of GE Healthcare. Of course, just like Xerox and copy machines, there are other manufacturers of SPR equipment.
Target: That to which one wishes to bind a ligand to modulate some biochemical activity in order to achieve a pharmaceutical effect, hopefully with clearly defined IP. Targets can be proteins, nucleic acids, or any other biological entity.
X-ray Crystallography: Method which uses the wave-particle duality of atoms to generate data on the binding and structure of ligands.

Request for Help: Seminal Papers in FBDD

Daniela, Sandra and Antonella from Menarini are writing a book chapter on FBDD. They would like to insert a timeline showing the seminal papers in FBDD that established the scientific bona fides for the use of FBDD.So, this is your chance people, send in the papers you think are crucial to the scientific validation of FBDD. Please include complete citation and what the paper establishes and why it is important.

Two easy ones:

Shuker, S. B., Hajduk, P. J., Meadows, R. P., and Fesik, S. W. (1996) Discovering High-Affinity Ligands for Proteins: SAR by NMR, Science 274, 1531-1534.
This demonstrates a start to finish process for prosecuting fragments. It is especially important in that it also establishes the primacy of having binding information to help drive medchem decisions.

Hajduk, P. J., and Greer, J. (2007) A decade of fragment-based drug design: strategic advances and lessons learned, Nature Reviews Drug Discovery 6, 211-219.
This paper compares and contrasts FBDD vs. more traditional lead-like, HTS screening. It clearly demonstrates the advantages of FBDD in generating high quality hits with a better chance of progressing.

Now you all...

26 July 2008

C&EN Cover Story on Fragments

Hi all,

I thought I’d highlight an excellent article on fragment-based lead discovery that appeared as the cover story of C&EN this week.

The story discusses the background of the field, current practice, and very recent industry developments (and I’m not biased for being quoted!).

Also, anyone want to go on record as to when we can expect the first fragment-derived drug to reach market?


24 July 2008

The Future of Fragment Blogging

Or should I say Fragging? Frogging? I will leave Fragonomics as my contribution to the scientific literature.
After some discussion, we have settled on how we are going to utilize this blog. First off, we are going to focus on fragments. PERIOD. We are working with the Structure-based Drug Design blog to have some synergies and limit overlap. As other blogs, forums, etc. come on line we will link to them.

So what about the format for this blog? Some ground rules first:
1. Assume anything you say here is disclosed. There is no confidentiality.
2. As my Latin teacher used to say, "The only stupid questions is the one you never ask."
3. As travel is being restricted across the board, virtual discussions will be the primary way to speak with colleagues. Utilize the tool.
4. This is non-commercial; blatant advertising will get you banned. Companies are of course allowed to share discoveries, as is anyone else.
5. This list is subject to change at any time.

As to format and content, we are planning on having a few "associate editors" who will post entries. Each associate editor will be a subject matter expert in a given general area. They will not necessarily be writing our content; our plan is for you the readers of the blog to write it. If you have a question, write it up and submit it. There will be links to the side to do this.

Appropriate content will be:
Questions of specific and general interest?
Opinion pieces
Invited pieces
Other things I haven't thought of.

Questions of content that need to be discussed are:
Changes in company strategy (this site is closing, or that company is axing this group, etc.)
Job openings or positions wanted.
Any others?

In order for this lively experiment to work, we need it to have engaged, interested readers. Please, let me and the other editors know what else we can do to make this work for you.

If you are interested in being an associate editor, we still have a few openings. Just let me know.

09 July 2008

Primary Screening

What are people thoughts about primary screen methodology?

NMR, X-ray, Biochemical, MS, SPR, etc.