23 April 2013

Poll: how many atoms are too few?

Last year we asked how large a fragment you would include in your library, but the related question, how low will you go, is also interesting (see poll to right).

Azaindole, with 9 non-hydrogen atoms, has been the starting point for more than one clinical compound, and 5-atom acetohydroxamic acid also figures rather prominently in fragment history, but would you include something this small? How seriously should we take the Rule of 1?

5 comments:

Dr. Teddy Z said...

Great poll. My thoughts which I will share while polling is active is "9-10" in your general library. Why, you ask? For a good LEAN compound (>0.3) with 10 heavy atoms, it has a KD of 1mM. 9 HAC gives you ~2mM. Going to 8 HAC gives you 4mM. While there are methods that can robustly detect these, I would hope that you find something with significantly better affinity. For example, 12 HAC with 0.3LEAN gets you into the 200 or so uM range.

Anonymous said...

Just to be clear here, you're talking about the number of non-hydrogen atoms (heavy atoms), right?

Dr. Teddy Z said...

Yes

Morten Grøftehauge said...

But hydrogen bonds are stronger than van der Waals forces. Even though binding sites don't like water and will give you free energy to displace it I would still expect an oxygen or nitrogen (or halide for that matter) to contribute more to the binding affinity than a carbon.

Dan Erlanson said...

Blogger is behaving like all too many governments and "losing" votes, so we've switched to Polldaddy. Apologies to those of you who voted on April 23 - please vote again.