15 October 2014

When a Fragment is DEFINITELY not a Fragment

There are lots of papers that use "fragments" or "fragment approaches".  I find a lot of computational papers do this, is it because FBDD has won the field, or its sexy?  Well, in this paper the authors take an interesting spin on the term fragment. For many targets (particularly PPI), peptides are the only tool to assess binding, or the best binders.  However, despite a small vocal minority, I think most people don't consider peptides to be drugs, but instead good starting points.  The REPLACE (Replacement with Partial Ligand Alternatives through Computational Enrichment) method is used to identify fragments for the CDK2A system to identify fragment alternatives to N-terminal portions of the peptide and especially the crucial arginine residue.  As I say, repeatedly, Your Computation is only as good as your Experimental Follow up

This group took a very cautious approach to the initial modeling, understanding that PPIs are difficult to study via computational methods.  They used crystal structures of FLIPs (Fragment Ligated Inhibitory Peptides) and modeled in the compounds against subunit B and D.  Subunit B gave better results and so that was used for further modeling.  [I hate this kind of stuff, strikes me as wrong.]  After further work, they concluded that the modeling was validated and would be predictive for new compounds.  Then designed a library based on a pharmacophore model using scaffolds phenylacetate, five member heterocycles, and picolinates.  
Modeled Compounds.  Cyclin residues have three letter code, peptides one letter codes.  The solid lines show interactions between acidic cyclin D1 residues and the piperinzinylmethyl group of the inhibitor.
They then, bless their hearts, made some compounds. 
In the end, they showed that it is possible to turn peptides into small molecule-ish compounds.  Please note these activities are in millimolar!  So, even with the current debate as to what PPI fragments should look like, I find it very hard to believe that these molecules are in anyway fragments.  Grafting a fragment looking something onto a big something is not "Fragment based Discovery". 

4 comments:

Dan Erlanson said...

I think the values in the tables should be micromolar (as stated in the text of the paper), not millimolar (as actually shown in the table), and since the researchers used detergent in the assay these are probably real.

I actually don't have a problem with the fragment label. Ultimately, fragments are a state of mind: if fragment-sized molecules are used at some point, and you get to new and useful chemical matter, the tent is big enough for all. I am reminded of Mark Whittaker's "fragment-assisted drug discovery" (FADD), where fragment methods are just another tool in the box.

Unknown said...

This appears to be a quick proof-of-concept style paper. Personally, I'd rather see faster publishing like this then have to wait longer for a refined story. As a quick POC, it might fall apart - but one has to start somewhere! As to whether these are fragments - it looks more like a fragment-growing method than it does an initial fragment finding method. I think medchems would just call it the same old thing we've been doing all these years...

Luca Sancineto said...

I'd like to know wether the typo was in the text or in the table.

Anonymous said...

A typo of mM is easy to make. If you want the lowercase mu, choosing the symbol font and typing "m" will give it to you. But if you copy and paste it, or it somehow gets transformed, your mu becomes an "m"--hence muM become mM. For that reason, I think it's advisable to use uM for micromolar.