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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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June 10, 2013

Getting Your Hands on All Those Three-Dimensional Structures

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Posted by Derek

The topic of making hit compounds, leads, and drug candidates that are less flat/aromatic has come up several times around here, and constantly around the industry. A reader sent along the following question: supposing that you wanted to obtain a decent collection of molecules with a greater-than-normal number of nonaromatic carbons and chiral centers, where would you find them?

Are there some suppliers that have done a better job than others of rising to the demand for this sort of thing? If anyone has nominations for good sources, or for places that are at least showing signs of moving in that direction, they'd be welcome. My guess is that fragment-sized molecules would be a good place to start, since they're (presumably) more synthetically accessible, and have advantages in the amount of chemical space that can be covered per number of compounds, but all comers will be considered. . .

Comments (12) + TrackBacks (0) | Category: Chemical News


1. Anonymous on June 10, 2013 11:30 AM writes...

We purchased original 3D compounds from Edelris in France.

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2. anon on June 10, 2013 12:02 PM writes...

The 3D fragment consortium deserves a plug:

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3. Anonymous on June 10, 2013 12:15 PM writes...

Natural product extracts

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4. Anonymous on June 10, 2013 12:32 PM writes...

Activate Scientific



(Hopefully the free advertising is OK? I've bought from all of these)

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5. Teddy Z on June 10, 2013 1:39 PM writes...

This is a subject of much debate in the FBDD community. [I agree that fragments are the best way to gain entrance into the 3D world of hit generation, but I am biased.] Particularly, if non-aromatic carbon percentages is a good way to determine "3D-arity". For example, toluene would be have a 0.14 ratio and I don't think anyone would consider it 3D. As #2 said above, the 3D consortium is making good progress in this area. At a FBDD conference this past April, both I and Justin Bower from the Beatson (part of suggested that principal moment of inertia (PMI) is a much better measure of 3D-arity. Chris Swain (he may be commenting as I write this) has updated his fragment library profiles with those properties. I would start with Chris's info first.

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6. Anonymous on June 10, 2013 2:16 PM writes...

Just import the sd file and convert them if you use Chemaxon products. Actually, I use a chemical library company out of Delaware, Frontier Scientific Services, Inc. and they have a great collection of molecules. You can search by structure, chemical properties and create libraries readily by physical chemical properties. The most important aspect is that the chemicals actually exist and can be ordered in any amount and even formatted into 96 well plates. And the quality of the compounds is exceptional and the diversity beats a lot the compounds I see on the internet.

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7. Anonymous on June 10, 2013 3:14 PM writes...

To #5: I'm not so sure about the usefulness of all gaussian curves from CMC.
They all pretty much look the same...

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8. SP on June 10, 2013 3:33 PM writes...

Just don't ask vendors for things enriched in sp3 carbons. One sent me a nice list of various aromatic cores with adamantyl side chains.

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9. LeProf_No1 on June 10, 2013 8:42 PM writes...

The Fragments of Life library from Emerald BioStructures (former DeCode Genetics) includes stereochemical rich fragments, based on naturally occurring substructures.

Marcaurelle and Clemmons at the Broad Inst seemed, at one point, to be taking leadership in hypothesis-driven use of diversity-oriented synthesis (DOS) arrays in early discovery...

And as background, Tan's written in a couple of reviews looking at the distinctive areas of property space occupied by natural products vs. traditional drug-like structures, see Current Opinion in Chemical Biology 2010, 14:308–314. Bottom line, it is seemingly not as simple three dimensionality, but a lot more's going on (back to the non-univariate theme).

That said, the utility of stereochemically rich fragments needs to be an active research interest, but is still without a great deal of careful, comparative research (of which I'm aware). Small synthetic houses clearly leading a charge to change the landscape—somewhat ahead of the data? of the discovery field in general? Though probably not of common sense, long-term.

As of '08, this was not my opinion solely; in a visit to Northwestern, Chris Lipinsky expressed a broad insider's perspective that DOS did not seem to be gaining traction among practicing pharma medicinal chemists. But 5 years is a long time...

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10. Chris Swain on June 11, 2013 2:49 AM writes...

Whilst there is great interest in fragments with more 3D structure the truth is you can only get so much 3D structure into 5-20 atoms. Some vendors have sought to explore 3D space be building in spiro fusion etc. but the consequence is that you can no longer rapidly follow up hits by simply buying analogues from catalogues. I suspect if you go down this route you will need to be prepared to commit significant chemistry resources earlier.
As an aside I wonder if the hit rates of rigid 3D structures may be much lower? and perhaps it might be better to screen flexible ligands that can adopt many 3D conformations, and then the chemist can optimise the ligand by building in constraints?

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11. Disc-Man on June 11, 2013 4:43 AM writes...

I agree with the last point of Chris Swain. The C-C bond rotation of biphenyls, bi-heterocycles gives a flexibility to bind in a certain conformation in the binding region which gives initial "Hit" level activity. As one goes further optimizing by bringing confromational constraints by tied-back with certain alkyl chain between the flat heteroaryl rings, or by having sterically demanding ortho groups or even internally H-bonded etc, one can get a better or proper slightly rigidified conformation to get a higher "lead" level activity. One can find such examples on peptidomimetics work by aryl based foldamers (work of Prof.Andrew Hamilton; Prof. Jeffery Aube; Prof Dale Boger; Andrew Wilson etc)

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12. A. Postdoc on June 13, 2013 11:41 AM writes...

Start searching and go from there.

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