01 June 2012

Poll results: how big are your fragments?

The poll results are in, and it looks like most of the 46 respondents look askance at fragments that are larger than about 20 heavy atoms:

Since each non-hydrogen atom adds about 13 Da to a molecule, this means fragment sizes are limited to about 260 Da, well below the Rule of 3. And some folks are even more stringent – 30% of respondents set an upper limit of 16 non-hydrogen atoms, or about 210 Da.

By way of comparison, I looked at the size of fragments in a fairly large (albeit somewhat dated) review. Of the 42 fragments reported, 79% consist of 20 or fewer heavy atoms, so clearly this is a fruitful area.

Of course, as the graph above shows, larger fragments have been discovered and advanced, but perhaps it is generally better to avoid the more obese fragments.


Morten Grøftehauge said...

20 x non-hydrogen atom weight + hydrogens = 260Da?
Is the 13Da really including hydrogens, oxygens, and nitrogens but not higher weight molecules? (I don't have access to Drug Discovery Today)

If we assume 1.5 hydrogens per non-hydrogen atom then that means that a single P, S, or Cl brings a 20 non-hydrogen atom fragment above 300Da (add 17Da for a P, 19Da for an S, 22.5Da for a Cl). That doesn't sound reasonable. On the other hand you can create most of what I would think of as a fragment at below 300Da (even methylene blue if you don't count the counterion).

You need a conditional poll - max number of non-hydrogen atoms and MW.

Dan Erlanson said...

I agree, this does seem on the low side. According to the paper:

Analysis of the Pfizer corporate screening data reveals that the mean molecular mass for a nonhydrogen ‘heavy’ atom in drug-like compounds is 13.286; thus, a compound with a 500 MW, contains on average 38 non-hydrogen atoms.

Benzene has an average non-hydrogen atom mass of 13 Da, so perhaps the Pfizer library circa 2004 contained a lot of aromatics.

It would be interesting to calculate this number for approved drugs.