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.
20 x non-hydrogen atom weight + hydrogens = 260Da?
ReplyDeleteIs 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.
I agree, this does seem on the low side. According to the paper:
ReplyDeleteAnalysis 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.