05 October 2015

Uninteresting GPCR Fragment Work...meant as a Compliment!!

There are certain movies that when they are on TV, I can't not watch.  I call these Broken Leg Movies (as in if I were laid up with a broken leg what would I watch).  As I have said, Road House is one, Apollo 13 another.  Its about America's blase attitude towards the amazing feat of putting men on the moon.  It takes a potential horrific tragedy (For those off you who haven't seen it, let me say (**Spoiler Alert**) don't worry it has a happy ending.) in order for America to care about men in space.  Which of course is in direct contrast to Pigs in Space (with Swedish Subtitles)! 

One of the field changing technologies is Heptares' STAR technology (for creating stabilized, soluble GPCRs).   We have discussed it often on this blog.  Well, they are back with another paper, this time working the voodoo they do so well on a Class C GPCR.  Negative allosteric modulation of the mGluR has the potential for significant medical impact in a variety of diseases.  In a relatively well trod drug space (there have been several molecules in late stage trials), an issue appears to be the acetylenic moiety in these drugs (which appears to be manageable).  So, non-acetylenic molecules would be desireable.  

To attempt to ligand this molecule, they screened 3600 non-acetylenic fragments using a radio-labeled assay.  This is in contrast to previous work where they used SPR. From this screen, 178 fragments were tested in concentration-response curves leading to "a number of promising" hits, including the compound shown below. 
Cpd 5.  pKi=5.6, LE=0.36
This compound was advanced using the tools you would expect (especially from Heptares): modeling, X-ray crystallography, medchem, and so on.  The final molecule is an advanced lead with excellent mGluR selectivity and in vivo activity, clean tox, and so on. 

This is excellent work, but "yawn".  I think it might be interesting to hear why they went with the radioligand approach, as opposed to SPR.  You could quibble that 5 is too big to be a fragment, but really?  Papers like this are uninteresting, we know its going to work.  The science is excellent, but I want to see the triumph out of tragedy.  Not here.  I want to congratulate Heptares for making an achievement like this paper perfectly uninteresting.  And I mean uninteresting as the very best of compliments. 


Anonymous said...

I think this almost every time I see a presentation by Astex. It all just seems so smooth....

Dan Erlanson said...

I disagree that this is "uninteresting." For one thing, there are some fun protein conformational changes, insights into molecular recognition (including the role of waters), and lots of nice medicinal chemistry.

More importantly though, reading papers like this is like watching Michelle Kwan perform a triple axel or Mikhail Baryshnikov perform a quadruple pirouette. Sure, it looks effortless, but practitioners can recognize the skill involved. And it's beautiful.

Dr. Teddy Z said...

Dan that is exactly the point I (obviously poorly) tried to make.