The recent rant about average molecular weight (AMW) leads
to the question of how large a molecule can be and still be called a fragment.
The Rule of 3 sets an upper limit of 300 Da, but perhaps we should think
instead in terms of number of heavy atoms. If we take Andrew Hopkin’s
calculation that the mean heavy atom adds 13.286 Da to a molecule, this would
set an upper limit of 22-23 heavy atoms, but is that already super-sized?
Now is your chance to weigh
in – please vote (on the right of the page) on the largest fragments you would
put into your library, and feel free to comment too.
I've indicated 20 for my vote but would like to stress that I believe that the distribution of molecular size (how ever you choose to measure it) is more important than the cut off values. I would build the core of a fragment library from smaller, more prototypical (low molecular complexity) fragments. One criticism that I would make of the rules of 5 and 3 is that both encourage mindless setting of cut offs without regard to distribution. The popularity of rules like these may actually be a symptom of a much greater malaise in Drug Discovery.
ReplyDeleteI agree with Pete...a cutoff like 20 (my vote also) needs to be fungible, and not a hard cut.
ReplyDeletei ALSO PUT 20 BUT IT IS THE CASE WHERE ALL ATOMS ARE CARBONS, OXYGENS AND NITROGENS. WHEN A MOLECULE CONTAINS SULFUR OR HALIDE THAN I WOULD REDUCE THE NUMBER OF HEAVY ATOMS SO IT WILL NOT EXCEED A MW OF 300
ReplyDeleteWouldn't it make more sense to email various fragment researcher's and ask them to send you histograms of non-hydrogen atom no. from libraries that they are happy with? Maybe ask them to do it also for the parts of the library only consisting of H, C, O, N to remove bias towards fewer non-hydrogen atoms when both are heavier atoms are present and a molecular weight cut-off is imposed.
ReplyDelete