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December 10, 2009
We spend a lot of time in this business talking about molecular scaffolds - separate chemical cores that we elaborate into more advanced compounds. And there's no doubt that such things exist, but is part of the reason they exist just an outcome of the way chemical research is done? Some analysis in the past has suggested that chemical types get explored in a success-breeds-success fashion, so that the (over)representation of some scaffold might not mean that it has unique properties. It's just that it's done what's been asked of it, so people have stuck with it.
A new paper in J. Med. Chem. from a group in Bonn takes another look at this question. They're trying to see if the so-called "privileged substructures" really exist: chemotypes that have special selectivity for certain target classes. Digging through a public-domain database (BindingDB), they found about six thousand compounds with activity toward some 259 targets. Many of these compounds hit more than one target, as you'd expect, so there were about 18,000 interactions to work with.
Isolating structural scaffolds from the compound set and analyzing them for their selectivity showed some interesting trends. They divide the targets up into communities (kinases, serine proteases, and so on), and they definitely find community-selective scaffolds, which is certainly the experience of medicinal chemists. Inside these sets, various scaffolds also show tendencies for selectivity against individual members of the community. Digging through their supporting information, though, it appears that a good number of the most-selective scaffolds tend to come from the serine protease community (their number 3), with another big chunk coming from kinases (their number 1a). Strip those (and some adenosine receptor ligands and DPP inhibitors, numbers 11 and 8) out, and you've taken out all the really eye-catching selectivity numbers out of their supplementary table S5. So I'm not sure that they've identified as many hot structures as one might think.
Another problem I have, when I look at these structures, is that a great number of them look too large for any useful further development. That's just a function of the data this team had to start with, but this gets back to the question of "drug-like" versus "lead-like" structures. I have a feeling that too many of the compounds in the BindingDB set are in the former category, or even beyond, which skews things a bit. Looking at a publication on it from 2007, I get the impression that a majority of compounds in it have a molecular weight greater than 400, with a definite long tail toward the higher weights. What medicinal chemists would like, of course, is a set of smaller scaffolds that will give them a greater chance of landing in a selective chemical space that can be developed. Some of the structures in this paper qualify, but definitely not all of them. . .
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