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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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April 5, 2012

What Makes a Beautiful Molecule?

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Posted by Derek

A reader sent along this question for the medicinal chemists in the crowd: we spend a lot of time thinking about what makes a molecule ugly (by our standards). But what about the flip side? What makes a molecule beautiful?

That's a hard one to answer, because, well, eye of the beholder and all that. One answer is that if it works well as a drug, how ugly can it be? (See the recent post here about the ugliest drugs in that light). Then there are all sorts of striking molecular structures that have nothing to do with medicinal chemistry, but for the purposes of today's discussion, I think we should rule those out. So, what makes a drug molecule (or candidate molecule) beautiful?

Size matters, for one thing. It may be my bias towards ligand efficiency, but I'm more impressed with potent, selective molecules that can get the job done with lower molecular weight. And you know that in a huge structure, a lot of the atoms are just scaffolding to get the business end(s) of the molecule in the right place, and I can't see giving points for that.

Points should also go for originality. I enjoy seeing a functional motif that hasn't turned up in a dozen other drugs. That may be because I can imagine that the team that developed the compound probably ran through the more usual stuff first and ended up having to go with the newer-looking group, in spite of their own reservations about what might happen. For similar reasons, I also have a bias towards three-dimensional character. Drug binding pockets are generally 3-D (and chiral), so a compound that takes advantage of those seems more elegant than a completely flat structure. (Although you can argue that a flat structure that works is easier to make, and that's definitely not a trivial consideration).
Escitalopram.png
These tend to lead me, when I look though tables of drugs, to CNS ligands, and perhaps that reflects the influence of my first few years in the industry. But for whatever reason, something like escitalopram just looks like a drug molecule to me. As came up in the "ugly drug" post, though, it's instructive to look over a list of, say, the 200 biggest-selling compounds and realize how many structures a person can find aesthetic fault with. Which shows you how far you can get with aesthetics in this business. . .

Which reminds me: coming soon is a large post with graphics of many of the nominated compounds in the "ugliest drug" category. It'll be worth looking them over, and reflecting that they're out there treating patients and making money.

Comments (30) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. PPedroso on April 5, 2012 8:07 AM writes...

Memantine compacteness is also somehow beautifull...
However it lacks the efficacy that we wanted it to have!

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2. PPedroso on April 5, 2012 8:13 AM writes...

However for beuatifull simplicity I will put my money on:

Pregabalin
Niacin

:)

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3. Rick Wobbe on April 5, 2012 8:26 AM writes...

Derek, You call something with a triple bond and a stereo center beautiful? I must've hung out with the wrong med. chemists.

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4. anon the II on April 5, 2012 8:43 AM writes...

@ Rick Wobbe

I agree with Derek. A stereo center is always nice for the reasons mentioned and for the fact that you can test the enantiomers. If you don't see a good separation of activity, you probably have a bad lead or a bad assay.

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5. processchemist on April 5, 2012 8:44 AM writes...

Escitalopram: and here we are... chiral switch from Citalopram and all the readers with more than 20 years in this industry will recall something about the C-C coupling toolbox of the "golden age"
1) Wittig /Hormer-Hemmons
2) Grignard + ketone-aldehyde-ester-whatever

And when you use grignards on a carbonyl, you end up with a stereocenter, so with much more chirality to deal with (racemates/couples of enantiomers).

The standard Suzuki/Buchwald toolbox is faster, simpler and totally a-chiral... We talk recently about Sharpless because of click chemistry etc, but the name of the guy is linked to an asymmetric epoxydation.... when did you perform your last epoxydaxion?


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6. anon the II on April 5, 2012 8:45 AM writes...

@ Rick Wobbe

I agree with Derek. A stereo center is always nice for the reasons mentioned and for the fact that you can test the enantiomers. If you don't see a good separation of activity, you probably have a bad lead or a bad assay.

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7. ROGI on April 5, 2012 8:47 AM writes...

#3 Rick

Yeah,like a beautiful woman, it's looks simple, yet complex in its efficiency. Best of all, when you engage it, it plays with your head and emotions and, come on...it has off target repurcussions that you would never have dreamed of unless you reeeeally wanted tit, uhhh.. it.

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8. UICAlchemist on April 5, 2012 9:16 AM writes...

Elegant Simplicity

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9. okemist on April 5, 2012 9:41 AM writes...

Beauty to the creator and beauty to the maker are 2 different things. Synthetic symplicity is BEAUTIFUL if you have to make more than 100g. But we always had the corollary if its easy to make then its inactive. To get away from structure, there is no more beautiful sight than to see a 36 inch neutche full of final product, ice colored crystals.

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10. johnnyboy on April 5, 2012 10:11 AM writes...

Interesting post. I can't comment on the esthetics of molecules, but I will say that in my own field , pathology, we have the same type of esthetic experience. Any pathologist will know the feeling when he happens upon a 'beautiful' (or 'cool') tissue lesion - however morbid that may seem to non-pathologists. Although what it is that makes a lesion 'beautiful' is as difficult to verbalize as it seems to be for molecules.

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11. UICAlchemist on April 5, 2012 10:11 AM writes...

Be sure to draw a distinction between a molecule being Beautiful and Sexy. I think escitalopram has a nice combination of both. Sexy molecules strike your interest upon first glance. But beautiful one's hold your attention and have a better potential of making it to the market. Beauty is simplicity!

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12. Hap on April 5, 2012 10:18 AM writes...

I am going to guess that having a beautiful lesion in a pathologist's sample is not really beneficial to the original possessor of the tissue. At least the people that make a beautiful molecule can get credit for it (although so can the person who prepared the sample).

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13. milkshaken on April 5, 2012 10:23 AM writes...

beauty is in the eye of a shareholder

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14. CMCguy on April 5, 2012 1:02 PM writes...

As a process chemist I can't help but quickly move beyond any aesthetic attraction I might see to "can I make at large scale with starting materials that would be widely available".

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15. bbooooooya on April 5, 2012 1:19 PM writes...

Sucrose. Aesthetically pleasing, made on megaton scales, and ever so tasty.

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16. David Borhani on April 5, 2012 1:33 PM writes...

It's hard to beat Li+ (Li2CO3) for ligand efficiency, synthetic accessibility, and beauty (in the Greek "Music of the Spheres" mode). Or is that too "simple"? ;-)
-- David

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17. Vader on April 5, 2012 3:29 PM writes...

Beautiful drug molecule? Metformin works. Simple, elegant, and effective.

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18. hopeless on April 5, 2012 5:42 PM writes...

Have some high standards please, folks.

To be qualified as beautiful drug molecule, it should have clean designed structure, elegant synthesis to make and superb efficacy.

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19. JF on April 5, 2012 7:17 PM writes...

The hydroxy ethylsulfonamide isosteres invented at Searle in the early 90's (for which Derek's company paid a royalty for the first 2 Vertex / GSK compounds) HIV protease inhibitors was clearly very good resulting in amprenavir. phosamprenavir and Prezestia (a now J&J compound). This was clearly one of the most concise and easily prepared potent HIV-Protease inhibitors. Ellerman at Berkley did a zombiechem study on it that essentially covered ever compound Searle had ever claimed to help his tenure and Ghosh seems to think he invented the molecule. It is far more concise than any of the first generation protease inhibitors and is one of the 2 that are billion dollar a year drugs

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20. Rock on April 5, 2012 11:13 PM writes...

I have two picks:
Sitagliptin (Januvia) and varenacline (Chantix).

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21. Anonymous on April 6, 2012 4:00 AM writes...

I thought all you had to do was deuterate someone else's molecule to make it beautiful........

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22. petros on April 6, 2012 8:32 AM writes...

Deuterium is the new silicon, that was also going to be an easy switch!

Surely aspirin is beautiful. Easy to prepare, very useful and still makes lots of money over 100 years on?

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23. LittleGreenPills on April 6, 2012 9:17 AM writes...

I agree with #25 about aspirin.

But from a purely structural perspective lovastatin and tadalafil both have a nice degree of structural diversity without being too complex.

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24. ScientistSailor on April 6, 2012 2:55 PM writes...

For ligand efficiency, it's hard to beat Abbott's PARP inhibitor ABT-888 (Veliparib) mwt = 244; Ki=4nM. and I find it's structure aesthetically pleasing.

Permalink to Comment

25. darwin on April 6, 2012 4:27 PM writes...

Dopamine-hard to argue.

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26. Secondaire on April 7, 2012 3:09 PM writes...

@18: yesss!

I agree with the consensus that "molecular beauty" (all semantics aside) is hard to put into tangible terms, partially because it's got so many facets. Does potency equal beauty? Structural novelty? Ease of synthesis? It's pretty subjective; for me, it's a combination of all three. I've worked with people who call molecules "beautiful" simply because they know they will be the first to synthesize them, while the rest of us think they're ghastly.

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27. Easy A on April 9, 2012 2:17 AM writes...

What does it say about us that we describe our molecules as beautiful and sexy?

1. that Medicinal Chemists are mostly men
2. we ought to get out a bit more (eg into the clinic where all that matters is what a drug does - not how it looks).

Feels like we're stuck in an episode of 'Mad Men'.

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28. Gnown on April 11, 2012 8:51 PM writes...

What about Eli Lilly's antipsychotic/anxiolytic candidate, LY-404,039? Lots of nice chirality there in a compact but densely-functionalized molecule.

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29. Yancey War on April 14, 2012 5:47 PM writes...

Delta-9-tetrahydrocannabinol is plenty pretty.

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30. simpl on April 16, 2012 8:46 AM writes...

What about symmetry?
We once had a company-internal fight between darodipine vs. the assymetric and later isradipine, which eventually got launched. I was rooting for the loser on grounds that symmetry is intrinsically elegant, though.

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