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March 26, 2010
Privileged Scaffolds? How About Unprivileged Ones?
The discussion of "privileged scaffolds" in drugs here the other day got me to thinking. A colleague of mine mentioned that there may well be structures that don't hit nearly as often as you'd think. The example that came to his mind was homopiperazine, and he might have a point; I've never had much luck with those myself. That's not much of a data set, though, so I wanted to throw the question out for discussion.
We'll have to be careful to account for Commercial Availability Bias (which at least for homopiperazines has decreased over the years) and Synthetic Tractability Bias. Some structures don't show up much because they just don't get made much. And we'll also have to be sure that we're talking about the same things: benzo-fused homopiperazines (and other fused seven-membered rings) hit like crazy, as opposed to the monocyclic ones, which seem to be lower down the scale, somehow.
It's not implausible that there should be underprivileged scaffolds. The variety of binding sites is large, but not infinite, and I'm sure that it follows a power-law distribution like so many other things. The usual tricks (donor-acceptor pairs spaced about so wide apart, pi-stacking sandwiches, salt bridges) surely account for much more than their random share of the total amount of binding stabilization out there in the biosphere. And some structures are going to match up with those motifs better than others.
So, any nominations? Have any of you had structural types that seem as if they should be good, but always underperform?
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