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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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December 10, 2009

Selective Scaffolds

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Posted by Derek

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. . .

Comments (6) + TrackBacks (0) | Category: Drug Assays | Drug Development | In Silico


1. anon the II on December 10, 2009 11:21 AM writes...

The answer to your first question is "Yes". Therefore, the rest is BS.

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2. barry on December 10, 2009 12:41 PM writes...

Within any "community" of biological targets, there are sub-sites for small-molecule binding that are largely conserved. It should surprise no one that the same scaffold--which provides functional handles in the right places, at the right angles--to connect these sub-sites keep coming back among the hits. Read Bartlett's papers on CAVEAT for a fuller exposition of the reasons.

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3. Guernseyman on December 10, 2009 12:51 PM writes...

The two questions I have in regards to studies like these are:

1) Is there any account made for the historical data being an artifact of aggregation?

2) Is the search for highly selective in vitro compounds really the best path for drug discovery?

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4. cynical1 on December 10, 2009 2:00 PM writes...

They found "community-selective" scaffolds for kinases? Wow, go figure. I would have never guessed. Did they find a lot of beta-lactams associated with beta-lactamase too?

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5. john n on December 10, 2009 5:24 PM writes...

Well nature has been there (steroids etc) so I wouldnt be surprised if the approach worked.

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6. cliffintokyo on December 10, 2009 8:16 PM writes...

Follow-up to #5

Derek, like this good thought-provoking post.
The *innocent* medicinal chemistry response to your wish (and many peoples) for smaller, simpler *scaffolds* [what a horrid word, can't we find a more scientific term that does not smack of a building site, thereby reinforcing the myth that med chem in pharma is just an assembly-line service to the biol screening slaves (aside to aside: its all about perceptions now isn't it?)] is that receptors are 3D, so we need a fairly sophisticated framework to get the necessary multiple, specific, productive interactions which, if we are lucky, lead to discovery of a biol act molecule with useful potency and selectivity.
Looking beyond steroids, which are really atypical/ yesterday's news (as far as research is concerned anyway; yes I know that they still contribute significantly to many firms' bottom lines, and justifiably so, in view of their efficacy), just see all the varied, beautiful, complicated 3D structures that nature has produced in order to do the business....

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