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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: derekb.lowe@gmail.com Twitter: Dereklowe

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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

« Drugs And Their Starting Points | Main | Nanoparticles and RNA: Now In Humans »

March 24, 2010

Privileged Scaffolds

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Posted by Derek

Here's a new article on the concept of "privileged scaffolds", the longstanding idea that there seem to be more biologically active compounds built around some structures than others. This doesn't look like it tells me anything I didn't know, but it's a useful compendium of such structures if you're looking for one. Overall, though, I'm unsure of how far to push this idea.

On the one hand, it's certainly true that some structural motifs seem to match up with binding sites more than others (often, I'd say, because of some sort of donor-acceptor pair motif that tends to find a home inside protein binding sites). But in other cases, I think that the appearance of what looks like a hot scaffold is just an artifact of everyone ripping off something that worked - others might have served just as well, but people ran with what had been shown to work. And then there are other cases, where I think that the so-called privileged structure should be avoided for everyone's good: our old friend rhodanine makes an appearance in this latest paper, for example. Recall this this one has been referred to as "polluting the literature", with which judgment I agree.

Comments (11) + TrackBacks (0) | Category: Drug Assays | Drug Industry History


COMMENTS

1. milkshake on March 24, 2010 11:48 AM writes...

the privileged scaffold concept is oversold by people who do combichem/parallel synthesis stuff and of course want to maximize the "drug-likeness' of what they are making.

I think the 'privileged scaffold" makes sense in CNS where you want to have a molecule that is already optimized to get into brain and has the right size, shape and grease/polar area to bind
to receptors there. Typically one sees pharmacologically-rich profile with such class, which is a good or bad thing.

Another example is aminopyrimidines and aminopyridines and also Sutent-like oxindoles, which are universal -enough that they could be elaborated to inhibit almost every know kinase. The problem there is that such elaboration is often done at cost of intolerably enlarging the molecule size and number of polar groups - which then ruins the drug properties.


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2. RB Woodweird on March 24, 2010 11:52 AM writes...

If a scaffold is "privileged" because it appears as a template in more than one endogenous ligand, then isn't building a drug on that template an invitation to cross-reactivity? Shouldn't the ultimate silver bullets be built on scaffolds the nontarget receptor systems have absolutely no interest in?

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3. Anonymous on March 24, 2010 1:49 PM writes...

fyi, the latest issue of Nature has a story on the Sirtris controversy. it cites (indirectly) some of the reporting on this blog.

http://www.nature.com/news/2010/100324/full/464480a.html

Permalink to Comment

4. anchor on March 24, 2010 2:44 PM writes...

#2 : Well said but your right and wrong. Understand that you need a quick platform to study the biology, efficacy and other things, if your company is initiating a therapeutic area. Prior scaffold can be helpful in this regard. As for off-target activity, it can be dialed out. I think "priviliged", scaffold design can serve the purpose well and working in parallel, If you come out with a new lead, then you have a head start.

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5. Pat Pending on March 24, 2010 3:22 PM writes...

You may have problems finding freedom-to -operate and patentable space within a generic "privileged scaffold" molecular space.

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6. Medchem23 on March 25, 2010 3:09 AM writes...

This fits in the same category as LE and various other med chem dogmas. Basically people trying to carve a little niche for themselves by hyping up a bit of pseudo science.

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7. chris on March 25, 2010 3:39 AM writes...

Klaus Mueller gave an interesting talk at the 2009 Cambridge Medchem meeting in which he described their work to define the requirements for a "privileged structure", "Small, non-planer structures with robust conformations that provide interesting 3D exit vectors for substitution, with drug-like properties and ideally readily accessible synthetically. He talked mainly about 7-membered rings in which restraints (annulated rings, amides etc) gave clearly defined structures which he illustrated by small molecule and docked ligand crystal structures.

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8. UK Chemist on March 25, 2010 4:12 AM writes...

Privileged can also mean'we can't be bothered to think of anything esle'

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9. UK Chemist on March 25, 2010 4:18 AM writes...

Privileged can also be med chem code for'we can't be bothered to make anything else'.

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10. SPRITY on March 25, 2010 9:20 AM writes...

All the privileged scaffold publications or presentations are simply a reflection of the problem that we do not know where the chemical space overlap with the biological space. The problem was demonstrated in the early days of the combichem era. With a few exceptions in which one could design biologically active molecules based on structure or mechanistic insights, such as kinases and proteases, it is extremely difficult to come up with a hit. Small pharma or academic lab do not have access to large number of biologically active compounds collected through decades of med chem projects. The logical thing to do is to start in the known biological space. The whole purpose of the privileged scaffold library is to find a hit or tool compound as a starting point. One can deal with the selectivity or freedom-to-operate issues after demonstrating that the biological target is disease relevant. Med chem projects are always full of surprise. A novel hit does not guarantee that it is free of cross-activity. CYPs are not very picky enzymes after all.

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11. Sylvester Salmela on December 4, 2011 12:04 AM writes...

It’s really a great and helpful piece of information. I am happy that you simply shared this helpful information with us. Please keep us informed like this. Thanks for sharing.

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