I wanted to let people know that I'm working on a long, detailed reply to Donald Light's take on drug research, but that I'm also looking at a few other publication venues for it. More on this as it develops.
But in trying to understand his worldview (and Marcia Angell's, et al.), I think I've hit on at least one fundamental misconception that these people have. All of them seem to think that the key step in drug discovery is target ID - once you've got a molecular target, you're pretty much home free, and all that was done by NIH money, etc., etc. It seems that these people have a very odd idea about high-throughput screening: they seem to think that we screen our vast collections of molecules and out pops a drug.
Of course, out is what a drug does not pop, if you follow my meaning. What pops out are hits, some of which are not what they say on the label any more. And some of the remaining ones just don't reproduce when you run the same experiment again. And even some of the ones that do reproduce are showing up as hits not because they're affecting your target, but because they're hosing up your assay by some other means. Once you've cleared all that underbrush out, you can start to talk about leads.
Those lead molecules are not created equal, either. Some of them are more potent than others, but the more potent ones might be much higher molecular weights (and thus not as ligand efficient). Or they might be compounds from another project and already known to hit a target that you don't want to hit. Once you pick out the ones that you actually want to do some chemistry on, you may find, as you start to test new molecules in the series, that some of them have more tractable structure-activity relationships than others. There are singletons out there, or near-singletons: compounds that have some activity as they stand, but for which every change in structure represents a step down. The only way to find that out is to test analogs. You might have some more in your files, or you might be able to buy some from the catalogs. But in many cases, you'll have to make them yourself, and a significant number of those compounds you make will be dead ends. You need to know which ones, though, so that's valuable information.
Now you're all the way up to lead series territory, a set of compounds that look like they can be progressed to be more potent and more selective. As medicinal chemists know, though, there's more to life. You need to see how these compounds act on real cells, and in real animals. Do they attain reasonable blood levels? Why or why not? What kinds of metabolites do they produce - are those going to cause trouble? What sort of toxicity do you see at higher doses, or more long-running ones? Is that related to your mechanism of action (sorry to hear it!), or something off-target to do with that particular structure? Can you work your way out of that problem with more new compound variations without losing all of what you've been building in so far? Prepare to go merrily chasing down some blind alleys while you work all this stuff out; the lights are turned off inside the whole maze, and the only illumination is what you can bring yourself.
Now let's assume that you've made it far enough to narrow down to one single compound, the clinical candidate. The fun begins! How about formulations - can this compound be whipped up into a solid form that resembles a real drug that people can put in their mouths, leave on their medicine cabinet shelves, and stock in their warehouses and pharmacies? Can you make enough of the compound to get to that stage, reliably? Most of the time the chemistry has to change at that point, and you'd better hope that some tiny new impurities from the new route aren't going to pop up and be important. You'd really better hope that some new solid form (polymorph) of your substance doesn't get discovered during that new route, because some of those are bricks and their advent is nearly impossible to predict.
Hey, now it's time to go to the clinic. Break out the checkbook, because the money spent here is going to make the preclinical expenses look like roundoff errors. Real human beings are going to take your compound, and guess what? Of all the compounds (the few, the proud) that actually get this far, all the way up to some volunteer's tongue. . .well, a bit over ninety per cent of those are going to fail in trials. Good luck!
While you're nervously checking the clinical results (blood levels and tolerability in Phase I), you have more questions to ask. Do you have good commercial suppliers for all the starting materials, and the right manufacturing processes in place to make the drug, formulate it, and package it? High time you thought about that stuff; your compound is about to go into the first sick humans it's ever seen, in Phase II. You finally get to find out if that target, that mechanism, actually works in people. And if it does (congratulations!), then comes the prize. You get to spend the real money in Phase III: lots and lots of patients, all sorts of patients, in what's supposed to be a real-world shakedown. Prepare to shell out more than you've spent in the whole process to date, because Phase III trials will empty your pockets for sure.
Is your compound one of the five or ten out of a hundred that makes it through Phase III? Enjoy the sensation, because most medicinal chemists experience that only once in their careers, if that. Now you're only a year or two away from getting your drug through the FDA and seeing if it will succeed or fail on the market. And good luck there, too. Contrary to what you might read, not all drugs earn back their costs, so the ones that do had better earn out big-time.
There. That wasn't so easy, was it? And I know that I've left things out, too. The point of all this is that most people have no idea of all these steps - what they're like, how long they can take, that they even exist. It wouldn't surprise me if many people imagine drug discovery, when they imagine it at all, to be the reach-in-the-pile-and-find-a-drug process that I mentioned in the second paragraph. Everything else is figuring out what color to make the package and how much to overcharge for it.
That's why I started this blog back in 2002 - because I was spending all my time on a fascinating, tricky, important job that no one seemed to know anything about. All these details consume the lives and careers of vast numbers of researchers - it's what I've been doing since 1989 - and I wanted, still want, to let people know that we exist.
In the meantime, for the Donald Lights of the world, the Marcia Angells, and the people who repeat their numbers despite apparently knowing nothing about how drugs actually get developed - well, here are some more details for you. The readers of this site with experience in the field will be able to tell you if I haven't described it pretty much as it is. It's not like I and others haven't tried to tell you before.