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When Chemistry Meets Biology

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Chemists and biologists often regard each other with a mixture of suspicion, incomprehension, and amusement. We speak different languages, we work on different scales with different sorts of equipment, and we worry about different things. But as time goes on, we're finding ourselves pushed more and more into each other's labs. As a chemist myself, I can't add much to the literature about understanding biologists. But I can talk about what we chemists are (and aren't) capable of — and not all of us are up front about that.

We're victims of our own success — or maybe just of our own successful press releases. Synthetic organic chemists have made some really impressive progress over the years, and along the way we've made some really impressive molecules. It would be easy to believe that we can make pretty much anything that we set our hands to. And to a first approximation, that's true, but it depends on how many hands we're talking about. Many of the huge, complex natural products have been made by gigantic teams of grad students and postdocs, paid at the usual painful rates and working the usual painful hours. You can cross over any size canyon if you're willing to toss in enough grad students to eventually walk across their backs, but that's not the optimal solution.

So while we can make all sorts of insane molecules if we have to, the more relevant question is: what can we make in useful amounts, under useful conditions? That's the whole question that medicinal chemists constantly ask themselves in the drug industry. But for high-throughput screening programs, chemical genomics, and other diversity-driven applications, "useful" could be almost anything.

There are a lot of estimates of how many reasonable organic compounds exist. But all of those guesses are terrifyingly large compared to the total number of compounds made so far in human history. That's something that chemists sometimes forget, and that scientists in other fields may not know: that we've just barely touched the edges of what's possible. I can sit down with the databases, and if I can't draw a simple compound in five minutes that has never been reported, then I must not have had enough sleep the night before. It isn't hard.

Some of these structures must not be stable, but most of them surely are. It's just that we don't know any ways to make them. We're pretty bad at eight- and nine-membered ring compounds, for example, no matter what they're made of — and there are untold zillions of three- and four-membered ring structures that we've never touched. All sorts of interesting, unknown heterocycles would be worth exploring, too, if we just knew how.

But wasn't combichem supposed to solve this? Weren't there huge libraries of compounds made all over the place and screened for activity? It was, and there were. But in the end, it turned out that the screening hit rate for those combichem libraries was actually lower than the rest of a drug company's compound collection. Combinatorial chemistry is still around, but its practitioners are a much more sober bunch than they used to be.

The biggest and most impressive collections of compounds are surely in the vaults of the large drug companies. But having spent my career behind those walls, I can tell you that many are the screens that come up empty, even with millions of compounds running past the targets. And the kinds of targets that we'll need to address (protein-protein, protein-nucleic acid, etc.) are going to strain things even more. No, my fellow chemists and I will not run out of compounds to make — in fact, we're probably already behind!

Derek Lowe is an organic chemist by training who has worked at a number of pharmaceutical companies since 1989. You can check out his blog, In the Pipeline, at www.corante.com/pipeline.

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