04 March 2013

Poll Results--HAC vs. MW

Our poll asking what denominator people use for the ligand efficiency metrics.  This idea for this poll came from these posts at In The Pipeline.  Of the 38 respondents, 8 "don't need no steenkin' metrics".  Of the remaining 30 answers, 27 people use heavy atom count, 1 uses both, and only 2 use molecular weight. 

So, in terms of everyday atoms, I think people can agree that heavy atom count makes the most sense.  But, Derek is still trying to figure out what to do with heavy halogens.  Do halogens need to be treated differently?  My thoughts are that they don't in the hit generation (HG) stage, but in lead optimization stage they would.   I have always thought that ligand metrics are most germane to the HG stage and less useful once you are trying to optimize things like PK/PD properties.  If a heavy halogen, makes it from hit confirmation, hit expansion, and into lead optimization, it is most likely doing something, so why penalize it?  

Am I thinking about this too naively? 

1 comment:

Morten G said...

Crystallographers will tell you (repeatedly): "Look at the density!"

Bromide is about twice the volume of a carbon, not the 6 2/3 that mass comparisons would yield. So it can definitely make more hydrophobic vdW contacts but not as much as the mass suggests. And it can make a strong halogen bond which is cool.
I think the problems with the heavier halogens are different. If you look at Wilcken at al. 2012/2013 they show higher attrition rates for brominated compounds in the clinic and based on their presentation of the available drugs with iodines and their side effect profile... well maybe someone else will figure out that mess. I would ignore it.