21 October 2013

Tessera, Tessera Everywhere

A lot of papers come across the editorial desk here at Practical Fragments.  Most of them appear because of a keyword in a search, sometimes somebody says, "Hey did you see this?", and sometimes we miss them (so if you see one that you think is interesting, doesn't hurt to ping us).  I recently came across this paper.  Well, the first thing that struck me was my branding was working, my eminence (LOL) in the field is working its way into people's thought process; I mean seriously the first line of the abstract is the entire reason my company is called what it is.  So, with great interest I dove into the paper.  So, what is it about?  The authors describe a fragment library and its use in a chemogenomics approach against three diverse target classes: GPCRs, Ligand-gated ion channels, and a kinase.  

The authors propose that promiscuous hits are driven by desolvation.  Thus, they propose a new sub-field: Fragment-based Chemogenomics (which obviously is a subset of Fragonomics) which is:
"an approach to accurately characterize protein–ligand binding sites by interrogating protein families with libraries of small fragment-like molecules."
They constructed a library of 1010 fragments "inspired" by the Voldemort Rule: number of heavy atoms 22, log P < 3, number of H-bond donors 3, number of H-bond acceptors 3, number of rotatable bonds 5, number of rings 1.  They then applied some medchem filters followed by a scaffold diversity analysis. 81 novel scaffolds were purchased to supplement underrepresented scaffolds.  Very nicely, they also identified scaffolds that were over-represented and selected those with high "cyclicity".  Lastly, the removed any compounds that showed any aggregation or preciptitation in any of the (published or unpublished) biochemical/biophysical assays.  Honestly, I wish they were more explicit here. The chemical space seems to be well represented (not shown) with underrepresentation of small aliphatic ring systems.
Physicochemical Properties of Fragment Library
They then screened the library against their various targets and, as expected, were able to identify actives with different hit rates.
This figure shows selected (how selected and are they necessarily important ones?) properties of the actives for selective and non-selective hits.  [N.B.  I am pretty sure that the second graph in (b) should be MW, not LogP again.]  Why these properties and not all of them?  To me this smacks of hiding data that do not support the central thesis.  More than a half of their actives bind to one specific target; however, 44 bind to two targets, 12 to three targets, and 11 to four targets.  Interestingly, none of the actives bind to all targets, so while they tried for some promiscuity, they did not get anything truly promiscuous.  There is no correlation between hydrophobicity and non-selectivity which they conclude means for fragments, unlike lead-like molecules, non-selectivity is NOT driven by desolvation.  

They then discuss two different types of cliffs: affinity (where two similar molecules differ in their ability to have activity) and selectivity (where two similar molecules are active against different targets).  I must admit my naivete here, but these two cliffs appear to be what I know as SAR

I ended up wanting more out of this paper, but for a first attempt it lays the groundwork for future refinement.  Is it a new idea? No.  The whole reason I came up with the Fragonomics name in the first place was as a joke/rebuttal to the huge array of -omics that were underway at Lilly at the time: chemogenomics, genomochemics, and so on. I would hope that this paper is a prelude to a much larger analysis of all properties and their correlation to specficity and non-specificity, down to the level of side chain and scaffolds. 

**EDIT** Dan just pointed out that he already blogged this paper back in MAY!  That's a lesson for me to blog while jetlagged.  

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