Comes the question, in a comment to the last post: "How much value is added by computer simulations?" Arrr. That's not easy to answer. I'd say, in some cases quite a bit, but in the majority of cases, none at all. And whether the former make up for the latter is a mighty close call. I know that there are molecular modeling success stories out there, and I've been on a project that started off dramatically with a (subsequently validated) modeling prediction. But I've been on others where the modeling was a total waste of time and effort.

Those linger in my memory, and surely account for some of my sceptical feelings about modeling in drug discovery. More specifically, there are a some major intellectual mistakes that I've seen simulations lead people into. The first one is something I alluded to recently - the awful temptation to believe that if you've seen a model of your molecule docking into a model of your target protein, then you've seen your molecule docking into your target. You haven't, you know. You've just seen someone's best guess, and the odds are excellent that it's wrong. Make a few more analog compounds, and the wonderful model that explains it all is likely to take on an unhealthy spotted appearance.

Ah, but that refines the model further, you say. And so it does - until the next analog blows that one, too. Still more refined! We have to be getting close now! But you can go through cycle after cycle of this stuff, and that leads to another trap: running the project for the sake of refining the model. It's an easy one to fall into, and it can always be justified by imagining what you'd be able to do with a simulation that explained all your compounds simultaneously. But you're not going to get one of those. As far as I know, no one ever has. And while you're chasing it, you're likely as not wandering away from the real purpose of your project, which was to find a drug. Remember? Even a drug whose binding mode you don't really understand will do, you know.

And one more pitfall is the way that modeling can constrain your thinking. If you really believe you're seeing reality (the first trap, above), then you might start ruling out whole classes of potential compounds. After all, they don't fit the model - why make 'em? And that violates one of my laws of medicinal chemistry, which I think I need to assemble into a list of their own: never talk yourself out of making an easy compound. The number of drugs that have been found by tripping over them is much larger than the number that have been found by homing in on them mathematically. Until the modelers come up with some more convincing mojo, I'll stick with my stumbling style.