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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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February 26, 2013

Natural Product Fragments: Get Rid of the Ugly Ones Now

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Posted by Derek

Here's a paper at the intersection of two useful areas: natural products and fragments. Dan Erlanson over at Practical Fragments has a good, detailed look at the the work. What the authors have done is tried to break down known natural product structures into fragment-sized pieces, and cluster those together for guidance in assembling new screening libraries.

I'm sympathetic to that goal. I like fragment-based techniques, and I think that too many fragment libraries tend to be top-heavy with aromatic and heteroaromatic groups. Something with more polarity, more hydrogen-bonding character, and more three-dimensional structures would be useful, and natural products certainly fit that space. (Some of you may be familiar with a similar approach, the deCODE/Emerald "Fragments of Life", which Dan blogged about here). Synthetically, these fragments turn out to be a mixed bag, which is either a bug or a feature depending on your point of view (and what you have funding for or a mandate to pursue):

The natural-product-derived fragments are often far less complex structurally than the guiding natural products themselves. However, their synthesis will often still require considerable synthetic effort, and for widespread access to the full set of natural-product-derived fragments, the development of novel, efficient synthesis methodologies is required. However, the syntheses of natural-product-derived fragments will by no means have to meet the level of difficulty encountered in the multi-step synthesis of genuine natural products.

But take a look at Dan's post for the real downside:

Looking at the structures of some of the phosphatase inhibitors, however, I started to worry. One strong point of the paper is that it is very complete: the chemical structures of all 193 tested fragments are provided in the supplementary information. Unfortunately, the list contains some truly dreadful members; 17 of the worst are shown here, with the nasty bits shown in red. All of these are PAINS that will nonspecifically interfere with many different assays.

Boy, is he right about that, as you'll see when you take a look at the structures. They remind me of this beast, blogged about here back last fall. These structures should not be allowed into a fragment screening library; there are a lot of other things one could use instead, and their chances of leading only to heartbreak are just too high.

Comments (9) + TrackBacks (0) | Category: Chemical News | Drug Assays | Natural Products


1. Rafael Najmanovich on February 26, 2013 11:49 AM writes...

It would be extremely useful if you would map these molecules into their closest synthetically accessible molecules that maintain their attractive properties. This would be really useful for people like me that generally don't take into consideration how difficult, if at all possible, to synthesize molecules.

A second interesting thing here is, from a biological point of view, to identify the specific reactions and enzymes that bring about such beasts that cannot be easily synthesized.

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2. barry on February 26, 2013 1:56 PM writes...

looks like the early screening results against Hsp90. One quinone (geldanamycin) one oxirane (radicicol) and a bunch of resorcinols. None of them lead-like. But further screening got us a lead-like hit. And co-crystal structures using the non-leadlike hits did inform our med. chem.

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3. flatearther on February 26, 2013 2:41 PM writes...

It's a great idea to have 3D molecules in screening sets and everyone in modern med chem is or should be trying to get more 3D character in their molecules. Trouble is, nobody has told biological targets that fatty, flat aromatics are bad.

Biological targets are like people: give them a choice of lovely healthy, 3D molecules or a bunch of greasy, unhealthy aromatics and they choose the unhealthy option every time. Screen 100 flat fragments and 100 3D ones together and, let's assume you get a lovely 10% hit rate, - I wouldn't mind betting you get 18 aromatic hits and 2 3D ones. For HTS this can be a problem but for FBDD with its lovely high hit rate this is a great chance to get in good 3D space but you need to start with a good number of 3D fragments and avoid letting the temptation of the flat, fatty stuff seduce you.

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4. gippgig on February 26, 2013 4:21 PM writes...

If you want more polarity, more hydrogen-bonding character, and more three-dimensional structure, why not use a bunch of carbohydrate (in the very loose sense including amino sugars, inositol, sialic acids, etc.) building blocks? Nature certainly does.

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5. regani on February 26, 2013 5:19 PM writes...

@4 that has actually been done a couple of times by a few different groups using a carbohydrate as a central scaffold and decorating it with different chemical functionalities (e.g. aromatics, amines, acids, etc.) pointing in different directions, e.g. see review ChemMedChem 1(2006)1164. the drawback is that you always end up in a slightly higher molecular weight range with the carbodrate starting at 180 already, which can make them seem less attractive. but apparently you can get quite good activity and metabolic stability out of those types of molecules.
the company is still working in that area, I believe

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6. Dan Erlanson on February 27, 2013 9:30 AM writes...

Thanks for highlighting this.

The discussion on "two-dimensional" versus "three-dimensional" molecules is important, but I think the more urgent issue here is the fact that the molecules shown are likely to generate spurious signals. A 2D-molecule like 7-azaindole could lead to a drug (vemurafenib), while a benzoquinone will probably just lead down artifact alley.

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7. barry on February 27, 2013 10:10 AM writes...

re: gippgig
Carbohydrates buy solubility at the price of cross-membrane transport. Too hard to desolvate them. So they only go where there's an active transporter for them. That's fine if they're natural sugars. But chances of blundering into an active transporter go down as your small molecule is farther and farther from a natural sugar.

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8. ChristianPFC on March 4, 2013 5:11 AM writes...


Practical Fragments has a good, detailed look at the the work.

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9. Björn Over on March 6, 2013 3:07 PM writes...

I am the first author of this paper.

Please see my comment on the original post on Practical Fragments.

And yes: Nature sometimes does ugly things. If these structures fit MedChem criteria is another story, but how many approved drugs do?

We showed in this paper a starting point and a way to explore nature's divergent chemical space.
For avoiding to use the available 'ugly' structures you first need to synthesis the 'nice' ones. We did this for some and found a novel chemotype of type-III kinase inhibitors, based on the structure of the natural product cytisine.

I am sure that our representative assembly of virtual NP-fragments will have an impact on the generation of future fragment libraries.

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