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: Twitter: Dereklowe

Chemistry and Drug Data: Drugbank
Chempedia Lab
Synthetic Pages
Organic Chemistry Portal
Not Voodoo

Chemistry and Pharma Blogs:
Org Prep Daily
The Haystack
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
Realizations in Biostatistics
ChemSpider Blog
Organic Chem - Education & Industry
Pharma Strategy Blog
No Name No Slogan
Practical Fragments
The Curious Wavefunction
Natural Product Man
Fragment Literature
Chemistry World Blog
Synthetic Nature
Chemistry Blog
Synthesizing Ideas
Eye on FDA
Chemical Forums
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
Gene Expression (I)
Gene Expression (II)
Adventures in Ethics and Science
Transterrestrial Musings
Slashdot Science
Cosmic Variance
Biology News Net

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

Economics and Business
Marginal Revolution
The Volokh Conspiracy
Knowledge Problem

Politics / Current Events
Virginia Postrel
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

« Down The Chute in Phase III | Main | Things I Won't Work With: Triazadienyl Fluoride »

October 20, 2008

Fearful Symmetry?

Email This Entry

Posted by Derek

It’s worth examining your own scientific prejudices and biases from time to time, to see if they’re still valid. Of course, that begins with the difficult task of figuring out what they are – it’s hard to think of these things when you need them. So I try to make note of my presuppositions when I find myself acting by them, flagging them for later review.

One of these that’s come up recently is the bias that I (and many other medicinal chemists) have against symmetric compounds. (By that I mean palindromic compounds with a mirror-plane right down the middle of their structures). We tend not to make such compounds; we downgrade screening hits with that look to them, and if we start to work on one the first things we do is to desymmetrize it and see if it gets any better. Why?

I think that one reason must be that there aren’t many truly symmetric binding sites out there. Proteins, while they can have large-scale symmetric structures, are usually pretty twisty and heterogeneous on the scale of a drug-sized molecule. Even in the cases of real protein symmetry (a dimer of two identical subunits, say), your compound would have to be fitting into some very select spaces to be feeling that symmetrical environment perfectly.

So a symmetric drug molecule feels wrong, somehow unoptimized. But there’s no reason that its two seemingly identical ends have to be doing the same thing on each side. They could easily be binding to completely different residues, or in different ways – it’s worth remembering that the symmetric structure we draw on the board may not have much in common with the molecule’s real 3-D conformation: a few zigs and zags in the rotatable bonds, and things aren’t as balanced as they looked.

Perhaps we shouldn’t be so hard on these structures. I’ve crossed several of them off my lists over the years, but I think from now on I’ll give them more of a chance. Anyone with me?

Comments (17) + TrackBacks (0) | Category: Life in the Drug Labs


1. sjb on October 20, 2008 9:02 AM writes...

I know what you're saying, but a literal reading of your comments suggests you only want compounds with chirality - after all even things like ethanol are locally symmetric around the C-C bond on most timescales....

Permalink to Comment

2. milkshake on October 20, 2008 9:03 AM writes...

HIV protease is dimeric and its active site is C2-symmetrical. The reason why symmetric HIV protease in hibitors aren't in use is that a single-point mutation in the protease hits them twice

Permalink to Comment

3. Lucas on October 20, 2008 9:35 AM writes...

The argument I've always heard against symmetrical molecules is solubility. High symmetry tends to lead to nice stable crystals, and that high lattice stabilization energy sends solubility right down the toilet.

On the other hand, I've always been of the "anything's worth trying" school of thought, so I usually say go for it, and symmetry be damned.

Permalink to Comment

4. Dlib on October 20, 2008 10:31 AM writes...

Wisdom in action!! If only it could be scaled up ;-)

Permalink to Comment

5. Green Koala on October 20, 2008 10:54 AM writes...

Much of our biases come from historical experience, in addition to the scientific rationale that Derek mentioned. I can't think of any symmetrical drugs or candidates recently or historically off the top of my head that are symmetrical.

Can anyone provide any current or old examples?

Permalink to Comment

6. Ed on October 20, 2008 11:42 AM writes...

Mr Koala, I think a number of Smac mimetics are symmetric, such as GDC-0145 (genetech), GT-13065 (TetraLogic) and HGS-1029.

Permalink to Comment

7. Richard on October 20, 2008 12:06 PM writes...

Antabuse, Dipyridamole, Ethambutol, Felbamate, Pentamidine and Mitoxantrone are all symmetrical drugs in clinical use.

Permalink to Comment

8. great white north on October 20, 2008 1:47 PM writes...

Cis-platin is a pretty good example, i'd say.

Permalink to Comment

9. Jose on October 20, 2008 4:34 PM writes...

Huh; I admit antabuse has a specific target, but isn't really a designed mechanism drug- it works via toxicity, which is also true for cis-platin. They are both such outliers as to be not very relevant. Mitoxantrone, etc on the other hand....

Permalink to Comment

10. Daniel Newby on October 20, 2008 4:46 PM writes...

Several tricyclic antidepressants, such as amitritypline.

Chelating agents tend to be symmetric or nearly symmetric. E.g., EDTA.

Amantadine (1-aminoadamantane) has 120 degree rotational symmetry.


Pentaerythritol tetranitrate (PETN) has two distinct planes of symmetry.

Lithium! (Yeah, that's cheating ...)

Permalink to Comment

11. satan on October 20, 2008 5:46 PM writes...

suramin, sodium stibogluconate, valproic acid, , dapsone, probencid, sulfinpyrazone, phenylbutazone, many bisphosphonates, propofol, succinylcholine, diethylstilbestrol, many synthetic curare derivatives, Pyrantel pamoate, busulfan, Altretamine, Glyceryl trinitrate, among others..

many other like lidocaine,fluconazole, diphenhydramine, phenytoin, metformin are symmetrical or very close to symmetrical.

Permalink to Comment

12. milkshake on October 20, 2008 6:17 PM writes...

Fentanyl, Nifedipine, Diphenhydramine, Barbiturates, Phenytoin, Gabapentin, Valproic acid, Paracetamol, Haloperidol, Fluconazole.

Fentanyl and Fluconazole story are particularly good, as an inspiration to medicinal chemists

Permalink to Comment

13. Philip on October 20, 2008 8:29 PM writes...

In spite of all these examples, I tend to think your prejudice is basically correct. In the twisty way that I think of binding (related to information content), there is more information/mass in a chiral molecule, which would be an advantage in a chiral environment. This is a trend, not a rule. I suspect the wealth of examples cited arises from synthetic expediency. Mother Nature, who has more time on her hands, tends to go the chiral route.

Permalink to Comment

14. Bob Hawkins on October 22, 2008 11:02 AM writes...

In my painful experience, it is necessary to examine your prejudices when the precision of measurements improves by an order of magnitude. The failure to do so in a timely fashion cost me a year of grad school.

Permalink to Comment

15. Morten on October 22, 2008 4:51 PM writes...

How does symmetry affect entropy? It must affect it mustn't it?

Permalink to Comment

16. Steven on April 30, 2015 12:01 PM writes...

I was excited to discover this website. I want to to thankk
you for your time just for this wonderful read!!
I definitely liked every little bit of it and i also hace
you bookmarked to check out new things on your website.

Permalink to Comment

17. Steven on April 30, 2015 12:01 PM writes...

I was excited to discover this website. I want to to thankk
you for your time just for this wonderful read!!
I definitely liked every little bit of it and i also hace
you bookmarked to check out new things on your website.

Permalink to Comment


Remember Me?


Email this entry to:

Your email address:

Message (optional):

The Last Post
The GSK Layoffs Continue, By Proxy
The Move is Nigh
Another Alzheimer's IPO
Cutbacks at C&E News
Sanofi Pays to Get Back Into Oncology
An Irresponsible Statement About Curing Cancer
Oliver Sacks on Turning Back to Chemistry