14 January 2013

Poll Results - Hurray for Diversity

In our latest poll, we asked what kind of libraries people like, giving three options:
  • I like a maximal diverse library (SAR comes from follow up)    
  • I like diversity, but not at the expense of SAR (follow up is easier with some SAR)              
  • My target is teflon so any active fragment is welcome news.   
 60% of respondents like a maximally diverse library, 31% like diversity with some SAR, and 8% work of teflon targets, so any hit matter is welcome.  

The way I read this is that 60% of people don't consider the screen done when the first results come in.  In my eyes, the screen is over when there are actives identified with testable SAR hypotheses.  This is probably just my bias of having lived in a very resource constrained environment where follow up to a screen was a second serving of resources.  To me, this is great news; companies that are doing fragment screening are invested and not giving short shrift to these efforts. 

I would be curious to hear in the comments how people develop SAR with a maximally diverse library.  Do you just pick every available fragment that has the same central core and evaluate all possible side chains?  Would you apply a similarity cutoff of 0.9 or something?  How many compounds do you follow up with per active fragment?


Chris said...

I suspect the first act is to run a orthogonal screen to try and identify any false positives.
Depending on the screen, if binding information is available then this can be used to direct compound selection for the next round.
If there is no binding information I'd look to select compounds to test ideas. Cap acids, modify pKa, explore space, conformational restraints etc.

Pete said...

Confirming hits using an orthogonal assay technology is a good thing to do although there may be advantages in seeing if one can find compounds that are more potent in the primary assay. Even when a lot of close structural analogs are available, it may make sense to look beyond these at what I'll term 'pharmacophoric' analogs and what Chris has termed testing ideas. This is the essence of hypothesis-driven molecular design and the ability to detect weak binding allows you get useful information with out synthesis. It can be helpful to think about hypothesis-driven molecular design as framework for assembling SAR as efficiently as possible.

Dr. Teddy Z said...


Not really a rebuttal...

Rahul Patidar said...
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