05 June 2017

Poll results: what structural information is needed to optimize fragments

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?

1 comment:

Unknown said...

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.