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October 20, 2008
Fearful Symmetry?
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 (15)
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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 Comment2. 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 Comment3. 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 Comment4. Dlib on October 20, 2008 10:31 AM writes...
Wisdom in action!! If only it could be scaled up ;-)
Permalink to Comment5. 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 Comment6. 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 Comment7. 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 Comment8. great white north on October 20, 2008 1:47 PM writes...
Cis-platin is a pretty good example, i'd say.
Permalink to Comment9. 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 Comment10. 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.
Nitroglycerin.
Pentaerythritol tetranitrate (PETN) has two distinct planes of symmetry.
Lithium! (Yeah, that's cheating ...)
Permalink to Comment11. 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 Comment12. 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 Comment13. 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 Comment14. 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 Comment15. Morten on October 22, 2008 4:51 PM writes...
How does symmetry affect entropy? It must affect it mustn't it?
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