The quality of a fragment hit depends
on the quality of the library. Virtual screens can be done with billions of
compounds, but if you’re going to build a physical library you need to be pickier.
Researchers today are increasingly avoiding pathological molecules such as PAINs,
but even sticking to “reasonable” molecules leads to choice overload.
So for those building or
refurbishing their libraries, Practical Fragments launches a new poll. It’s
been almost five years since we’ve asked readers about their libraries, and the
current poll is our longest yet, with six questions.
The first three questions focus
on size: how large is your fragment library and what are the minimum and
maximum number of heavy atoms in each fragment.
Next, we ask about whether you
include chiral molecules in your library, and whether these are present as enantiomerically
pure compounds or racemates.
Chiral compounds can introduce synthetic challenges which may impede hit follow-up, so our next question asks whether
you consider synthetic tractability before adding fragments to your library.
Finally, building a proper
fragment library requires considerable time and resources, so you want to take
good care of it. Our last question probes how you store your fragment library. Note
that this question asks about your working library, the one that you screen and
access on a regular basis, not the master stocks which may be squirreled away as
solids in the deep freeze.
Please vote on the right-hand
side of the page. If you have multiple fragment libraries (perhaps one for crystallographic
screening and another for biochemical screening) feel free to vote for each;
you need to press "Finish Survey" at the end.
There are, of course, more complex
elements to library design that can’t be captured in simple multiple-choice
polls. For example, we’ve written previously about the importance of function
rather than functional groups, and the types of rings found in approved drugs.
If you have opinions about these or other subjects, please share.
The poll was already long so we
decided not to ask about library vendors, which we addressed in 2018. On this
topic too, please feel free to share your thoughts.
Happy voting!
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