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October 20, 2008
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?
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