Our latest poll asked “how much structural information do
you need to begin optimizing a fragment?” Over the past few weeks we received
143 responses, and the results are shown here.
Just over a third of you said that you wouldn’t work on a
project without a crystal structure, while nearly a quarter said you’d settle
for an NMR-based model. In other words, more than half of you demanded fairly
detailed structural data to embark on a fragment optimization campaign.
But consistent with continuing improvements in modeling,
almost a fifth said that a computational model would be just fine.
And perhaps most surprisingly, fully one quarter of you said
that SAR alone would be sufficient to begin optimizing a fragment. Presumably
this is driven at least somewhat by internal successes, and I look forward to
seeing these disclosed in meetings and publications.
All of these approaches are rapidly developing, and it will be
fun to revisit this poll in a few years to see whether crystallography
maintains its lead, or whether lower resolution methods gain dominance.
In the meantime, are there other topics you’d like to see
polled?
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1 comment:
How about before hit optimization?
This might have been polled, but I'd like to see how people stick to the so-called "rule-of-three" when assembling fragments for their library.
Practically, would you also start with fragments with sub-optimal aqueous solubility? This may depend on the size of the fragment, but I found for smaller fragments (MW ~ 200 or less), a solubility of 1 mM (with 1% DMSO in PBS) is usually not sufficient for functional assays since they often bind very weakly to the target.
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