Corante

About this Author
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: derekb.lowe@gmail.com Twitter: Dereklowe

Chemistry and Drug Data: Drugbank
Emolecules
ChemSpider
Chempedia Lab
Synthetic Pages
Organic Chemistry Portal
PubChem
Not Voodoo
DailyMed
Druglib
Clinicaltrials.gov

Chemistry and Pharma Blogs:
Org Prep Daily
The Haystack
Kilomentor
A New Merck, Reviewed
Liberal Arts Chemistry
Electron Pusher
All Things Metathesis
C&E News Blogs
Chemiotics II
Chemical Space
Noel O'Blog
In Vivo Blog
Terra Sigilatta
BBSRC/Douglas Kell
ChemBark
Realizations in Biostatistics
Chemjobber
Pharmalot
ChemSpider Blog
Pharmagossip
Med-Chemist
Organic Chem - Education & Industry
Pharma Strategy Blog
No Name No Slogan
Practical Fragments
SimBioSys
The Curious Wavefunction
Natural Product Man
Fragment Literature
Chemistry World Blog
Synthetic Nature
Chemistry Blog
Synthesizing Ideas
Business|Bytes|Genes|Molecules
Eye on FDA
Chemical Forums
Depth-First
Symyx Blog
Sceptical Chymist
Lamentations on Chemistry
Computational Organic Chemistry
Mining Drugs
Henry Rzepa


Science Blogs and News:
Bad Science
The Loom
Uncertain Principles
Fierce Biotech
Blogs for Industry
Omics! Omics!
Young Female Scientist
Notional Slurry
Nobel Intent
SciTech Daily
Science Blog
FuturePundit
Aetiology
Gene Expression (I)
Gene Expression (II)
Sciencebase
Pharyngula
Adventures in Ethics and Science
Transterrestrial Musings
Slashdot Science
Cosmic Variance
Biology News Net


Medical Blogs
DB's Medical Rants
Science-Based Medicine
GruntDoc
Respectful Insolence
Diabetes Mine


Economics and Business
Marginal Revolution
The Volokh Conspiracy
Knowledge Problem


Politics / Current Events
Virginia Postrel
Instapundit
Belmont Club
Mickey Kaus


Belles Lettres
Uncouth Reflections
Arts and Letters Daily
In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« Drug Companies Since 1950 | Main | Pfizer's R&D Productivity »

December 10, 2009

Selective Scaffolds

Email This Entry

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


COMMENTS

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.

Permalink to Comment

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.

Permalink to Comment

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?

Permalink to Comment

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?

Permalink to Comment

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.

Permalink to Comment

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....

Permalink to Comment

POST A COMMENT




Remember Me?



EMAIL THIS ENTRY TO A FRIEND

Email this entry to:

Your email address:

Message (optional):




RELATED ENTRIES
Gitcher SF5 Groups Right Here
Changing A Broken Science System
One and Done
The Latest Protein-Protein Compounds
Professor Fukuyama's Solvent Peaks
Novartis Gets Out of RNAi
Total Synthesis in Flow
Sweet Reason Lands On Its Face