01 October 2014

Safran Zunft Challenge

Dan has already hit the highlights of FBLD 2014.  I won't do the lowlights.  They were few and far between.  I will try to give some flavor of the conference.  If you missed it, they t-shirts given out had this as a design
This was designed by Lukasz Skora of Novartis.  It is keywords used here at the blog, sized by frequency.  That is pretty cool.  It also gives us an idea of what we are really talking about here.  I have some other "flavor of Basel pictures" posted here.  

The conference was excellent, just the right size to allow people to interact at a high level.  The dinner was especially good for this (and the unending wine/beer didn't hurt!).   I have been lucky this year to be at many conferences with many different people.  Damian Young at the Baylor College of Medicine Center for Drug Discovery (and recently of the Broad) has been speaking at all of them about his Diversity Oriented Synthesis (DOS) approach to generating fragments.  Well, this has bothered me, DOS is not Fragments.  Am I some sort of Luddite?  Am I being too purist?  Could be.  

Well, an eminent group of FBLD-ers was gathered around a table during the conference dinner, including Justin Bower and Martin Drysdale of the Beatson, Chris Smith of Takeda, the aforementioned Dr. Young, myself, Terry Crawford of Genentech, and Beth Thomas of the CCDC.  So, out of this discussion, comes the Safran Zunft Challenge, administered by Dr. Bower.  I bet Damian that his molecules are too complex to be "fragments".  What will this mean?  I am betting that a "bad" interaction is worse than a good one, that is going all the way back to the Hann Model.  

So, this one molecule from Damian's presentation.  I have nothing against it per se, but for illustrative purposes.  I bet that his molecules will not have a LEAN (pIC50/HAC) >0.3.  [This is the metric I like, Pete.  I understand the limitations.]  By FBLD2016, Damian expects to have data on his molecules (and he is looking for partners).  If I lose, I owe the undersigned a beer.  Below we have preserved for posterity the discussion and those who were there (no hopping on the beer bandwagon late people!).  

I also think this is a good way for us to discuss the ontology of a "fragment"?  To me, its not just size, it is more of its "nature".  Fragments rely on simple molecules, adding complexity even with small molecules, strips away the "fragment-ness", IMNSHO

11 comments:

Brandon Findlay said...

Who was Wolfgang Jahnke's post-doc? It seems kind of weird to focus more on the supervisor than the person who made the shirt.

Dr. Teddy Z said...

I totally forgot his name and I feel horrible. I am hoping someone knows the name, so I can edit the post.

Pete said...

Perhaps you could make the response of activity to molecular size the focus of your bet and you wouldn't have to worry about your arbitrary choice of reference concentration?

Anonymous said...

His name is Lukasz Skora.

Dr. Teddy Z said...

And fixed. TYVM Anonymous.

Damian Young said...

Teddy, thanks for framing the Safran Zunft Challenge. It made for some excellent and lively discussion in Switzerland. Come 2016 in Boston we will have the data to put this one to rest.

Dan Erlanson said...

I like the fact that DOS-derived molecules tend to look somewhat different than most commercial fragments. I do agree that they also appear more complex, and are thus likely to have a lower hit rate. That said, if they have better physicochemical properties and are easier to analog, this may be an acceptable trade-off. I look forward to seeing how the data shake out, and who wins the Safran Zunft Challenge!

Dr. Teddy Z said...

I should note that the molecule shown has NOT been tested, but instead that is what it will need to be active to have a LEAN of 0.3.

Pete said...

How does the bet work if some of Damian's compounds show LEAN greater than the chosen cut off? Is he allowed to use Ki or Kd to define the efficiency metric? How will you account for the uncertainty in the measured activity when settling the bet?

Anonymous said...

Gotta love those vinyl sulfonamides - nothing like some reactive fragments to spice up a collection.

So, unlike Dan, I'd bet on a higher hit rate!

Dan Erlanson said...

Good point Anonymous - the particular molecule shown does look a bit funky!