Click and Clack

A new paper describes how combining fragment classes that selectively react with each other can yield an inhibitor to a protein-protein interaction.

Most of you are probably familiar with the concept of “click chemistry”, exemplified by the Huisgen cycloaddition of azides and acetylenes to form triazoles, and defined earlier this century by K. Barry Sharpless and colleagues. The idea, put very simply, is to react two molecules selectively and reliably to generate a product in high yield. The approach has obvious applications to fragment-based ligand discovery, and in fact Sharpless and co-workers demonstrated that the enzyme acetylcholinesterase can catalyze the formation of an inhibitor with femtomolar potency, starting from two fairly large and potent “fragments,” one containing an azide, the other an alkyne.

The notion of using a protein as a template on which to assemble an inhibitor dates back further than click chemistry. Huc and Lehn used reductive amination between aldehydes and amines in the presence of carbonic anhydrase to capture molecules that interacted more strongly with the protein than did the starting materials, and the technology even formed the basis of a company, Therascope.

In the latest example of this line of research, Roman Manetsch and colleagues find that the antiapoptotic cancer target Bcl-xL is able to catalyze the formation of an inhibitor from fragments sporting thioacids and sulfonyl azides; the inhibitor itself was previously discovered using different fragment-based methods at Abbott. The reaction appears to be relatively fast, and works even in the presence of a small pool of sulfonyl azides.


The paper, published this month in the Journal of the American Chemical Society, is a nice proof-of-concept study, but it does raise practical questions. First, the authors report the use of only six sulfonyl azides and three thioacids. These generally need to be custom-made rather than purchased; how much of a barrier will this represent to other practitioners? Once assembled, how stable will these fragments be in long-term storage? Finally, the product acylsulfonamide is a rather special entity not commonly found in drugs, and with a limited range of bioisosteres (indeed, it was originally employed at Abbott to replace a carboxylic acid). Still, the paper does provide an interesting - if less conventional - method of fragment-based lead discovery.

It's Here

The biggest thing Ever!!!

By that I mean this
There is a link to buy it on the side of the blog. The book published on 17OCT2008 and is already getting great reviews. Here are a few choice ones:

"Fantastic dear, can you explain to me what you do again?" Teddy's Mom
"Cool." Teddy's Brother
"That's nice dear." Teddy's Wife.

WOW, with such enthusiastic support, the book will surely hit the New York Times Bestseller list.
Seriously, I think this is an excellent complement to the Erlanson/Jahnke book focusing on the real details of how to do FBDD. If you buy a copy, I will personally autograph it for you. If you buy it, and send a crisp, clean 20 $ bill to me, I won't.

FBLD 2009

Looking for a good conference next year? Check out FBLD 2009!

Some 250 of you had the pleasure of attending FBLD 2008 earlier this year in San Diego, one of the best conferences I’ve attended in my scientific career. The event brought a wide range of experts from a variety of experimental backgrounds. Held in a resort on a private island to encourage mixing, it felt like a Gordon Research Conference, but without the dorms.

The sequel will be held across the pond in beautiful York, an ancient university town with intact city walls, an 800 year old minster, and excellent restaurants and pubs.

Put September 21-23 on your calendar (with a special workshop on Sunday, Sept. 20), and submit your travel request now before your budget gets cut!

Are Biophysicists dogmatic or agnostic?

Here is a comment from this post:

Ever considered to use enzyme assays as a 1st line assay for fragment screening, then follow up with NMR or X-Ray AND SPR?

Does the job!

This of course is the inherent (and apparent) tension in FBDD. Biophysicists (those rascally folk trained in such things as NMR, X-ray, SPR) want to perform their chosen technique. Medicinal chemists are no different, they want to make molecules. Biologists want to run compounds. Everybody wants to do what they are trained to do: management rewards doing your job. DUH!!! Credit is doled out by the dropper, so there is never enough to go around; we have been trained to grab as much unto ourselves as we can. The tension is not inherent in the science, it's imposed upon us by management [edited out my really nasty comment about managment].
Is it the belief of non-biophysicists that biophysicists don't find value in data generated by other techniques, or don't consider them of sufficient value? I have encountered highly dogmatic biophysicists...as well as highly dogmatic medicinal chemists, biologists, etc. My favorite quote, and absolutely real, "Why would I need fragments, I know how to get molecules into the clinic." Guess how many post-POC compounds that person had to their credit. Three guesses: first two are wrong, and the third should be less than 1.
I think the best FBDD practitioners (and shoot, we need some sort of really cool name for us) or agnostics. High quality data is high quality data, doesn't matter where it comes from. In fact, my answer to the commenter above is "Of course, when resources allow, multiple, orthogonal data is always the answer." FBDD should be method agnostic, something I have always preached. A rising tide raises all boats; credit should go to a team, not individual members. And YES everybody gets a pink unicorn in my world.

Bacterial Paclitaxel from Fragments

The rise of new bacterial strains resistant to existing antibiotics has long been anticipated, but a lack of investor interest means few companies are doing anything about it. A nice exception is described in a recent paper in Science from UK-based Prolysis and collaborators at several other institutions. And they used fragment-based drug discovery.

The researchers started with 3-methoxybenzamide, which was shown several years ago to inhibit the bacterial protein FtsZ and inhibit cell division in Bacillus subtilis, leading ultimately to cell lysis. FtsZ is a distant relative of the mammalian protein beta tubulin, a target for such famous anticancer drugs as paclitaxel.


The paper does not discuss the details of the fragment-based methodology used; hopefully this will be published separately. What we do know is that after some 500 analogs the researchers arrived at PC190723, which is roughly two thousand-fold more effective against B. subtilis as well as a host of staphylococci, including such nasties as multi-drug-resistant Staphylococcus aureus (MDRSA). Molecular modeling and mutagenesis data suggest that the compound binds to the region of FtsZ corresponding to the taxane-binding region of tubulin. The compound was also able to completely protect mice from an otherwise lethal challenge of S. aureus.

This is a nice story on several levels, as befits its publication in Science. First, it describes a new lead series against deadly bacteria. Second, it validates a new drug target and provides a new tool compound for exploring microbiology. And finally, it again demonstrates the power of fragment-based drug discovery to generate useful, novel molecules. Indeed, perhaps the fact that the fragment-origins of PC190723 are merely a side note as opposed to a central focus of the publication shows that the technique has become main-stream.