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April 5, 2012
What Makes a Beautiful Molecule?
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).
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.
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