I’ve been in this business for almost 19 years now. That means that the drugs that were discovered during my first few years of work are now either on the market or expected to be there soon. Fine, I spent my first eight years at Schering-Plough, so what do I see when I look back? There’s ezetimibe, discovered by sheer chance (but developed by sheer determination, though) and the thrombin receptor antagonist, squirrelly chemical matter from a failed Alzheimer’s program, a compound that a lot of medicinal chemists wouldn’t have even made in the first place. Well, now.
This is not a whack at Schering-Plough. Far from it. These are compounds that any organization would have been glad to find, but they weren’t exactly found by direct routes. This is a general phenomenon. You’d think, surveying the industry, that a lot of drugs are discovered, at least partly, by outright luck. And as far as I can tell, you’d be right. Realizing that tends to bring on several different reactions, depending on your world view:
That can’t be right. I’ve seen this one mostly from people outside the immediate realm of drug discovery, well-meaning people who just can’t believe that this is how it works. The harm comes when these well-meaning folks decide that the problem is that the industry is just behind the times, and that we wouldn’t have to do it this way if we’d just adopt some modern management techniques – ISO whatever-thousand, umpteem-sigma, Quality Assurance Tiger Team Circle Continuous Improvement Metrics, or what have you. Harm generally ensues.
That shouldn’t be right. Some of the people in this category are actually offended by the sight of luck calling so many of the shots, while others are just hoping for a more productive way of doing things. A lot of computational approaches have come from this attitude: “We wouldn’t have to run around stumbling over stuff if we’d just turn on this great new flashlight that’s just been invented” Nothing’s quite illuminated the landscape in the way that people have hoped, though, although efforts continue, as they should.
OK, if we’re stumbling around, let’s stumble faster. This is the basic idea behind the improvements in high-throughput screening and combichem in the late 1980s and the 1990s. For a while, the more optimistic folks thought that this would be enough: just crank out millions of compounds, and the drugs would come – they’d have to. It didn’t work that way, partly because the space of usable chemical structures is much, much larger than we can usefully deal with. But that’s not to say that cranking out more compounds and screening them more quickly isn’t a good idea – it’s just not the good idea.
Well, stumble more purposefully, then. I think that this is where most drug discovery organizations are (or should be). You admit that luck has a big role to play, but you go for the “Fortune favors the prepared mind” approach. Don’t rely just on random runs of odd structures to fill your screening banks – but be sure to put some in, because you never know. Turn over every rock – but recognize that you can’t turn over every rock everywhere, so try to pick the most likely place to start.
The problem with this approach is that it doesn’t promise much, at least compared to the various You’re Doing It Wrong approaches, and it doesn’t make a very compelling PowerPoint slide. But although it’s the blood-toil-tears-and-sweat option, I think that for now it’s the right one. Until something better comes along, that is, and the fascinating problem is that something better is always coming along. Given this state of affairs, why shouldn’t it?
I have no room to talk, of course. I can be as much of a sucker as the next medicinal chemist for some new approach that’s going to change everything – mainly because I look around and realize that a lot of what we do would be better off changing. All the wasted effort. . .you can get downright melancholy if you look at the business from the saddest angles. For all my self-proclaimed realism, I probably have more of that second response in me than I like to admit. The idea is to keep trying for something dramatically better, while realizing that even a smaller improvement would still be worth a lot. . .