Derek Lowe describes how the drug discovery process really works and why critics who perpetuate the myth that the NIH discovers targets and drugs before the pharma industry ruthlessly exploits the taxpayer don’t know what the hell they’re talking about. Here’s a snippet but if you’re interested in this kind of thing because you don’t know much about it, you should read the whole post:
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.
That’s just the start of the problem as Derek goes on to point out. This is usually where the drug designers get involved, sifting through the information that comes from the screens, clustering the compounds that show activity, doing searches on in-house and commercial databases, finding the common features of the hits to determine if there’s a reason why they’re active, and proposing modifications to those lead series (that the chemists will ignore). You do this on enough projects and you become a very good pattern spotter without really trying. But that was only a small part of my job. Most of the projects I’ve been involved in go on for years. It’s a very iterative process and sometimes, the project takes off on tangents It’s like untying a giant knot with lots of little subknots that sometimes need to be solved first.
The bottom line is that as valuable as the NIH contribution is, it’s usually the 1% inspiration that leads to the drug industry’s 99% perspiration.
Politicians should spend a little time interviewing the drug discovery people. I don’t mean the executives or the lobbyists. I mean the people who actually do the work. It appears that there is a lot of mythology to dispel still. And without a more complete concept of how drug discovery works, it’s difficult to craft policies to make pharma research work for patients, government and businesses.
If I might make a suggestion to Derek, visual aids might be useful. Just dig a couple of slides from your latest pre-project team meeting and modify the names of the targets. People will not really grasp what is involved until they see it.