Bloomberg has a feature on Relay Therapeutics, who are just a few blocks away from me (and where several former colleagues of mine work). It’s a nice writeup, and also features a (relatively rare) spotlight on David Shaw of D. E. Shaw research. He’s one of those guys that you’ve likely never heard of unless you’re pretty into Wall Street stuff, but he and the firm he founded are a good example of how important things don’t always make the newspapers (see below). If his name (or that of Jim Simons) rings no bells, that’s probably how they like it.
First, Relay. As the article says, their big thing is molecular dynamics. That’s easy enough to explain in concept, but in practice it’s. . .nontrivial, as we applied-science types like to say (while exchanging significant glances). Even many people outside of drug discovery, chemistry, or science altogether have heard of the idea of using a computer-aided model to “dock” drug molecules and see which ones fit better than others. This has been discussed in the popular press since at least the early 1980s, with the result being that some people think that’s how all drugs are discovered.
Far from it, though, as practitioners will tell you: docking-and-scoring has come a long way, and can be useful depending on the circumstances, but it’s far from a royal road to wonder drugs. There are so many things that are tricky about evaluating the energy gained and lost as a small molecule interacts with a protein (and with the surrounding solvent) that the error bars can start to creep up on you rapidly – and what’s worse, you many not even realize that they’re doing so. And that applies even when you have the right three-dimensional conformations for the protein and for the small molecule (and you don’t, not always, nor do you necessarily realize it when that’s happening, either).
Note that in that case we’re talking about a relatively static situation, which in most cases just isn’t realistic. Small molecules move around, and solvent molecules do little else but move around. And Lord knows that protein binding sites can be flexible, too. The old “lock and key” model suffers from our experience of locks and keys being made out of rigid metal. If they were made at least partially out of pizza dough we’d have a better mental picture. So bringing in molecular dynamics (MD) has the potential to help out, because that explicitly tries to calculate all these motions across the whole binding event. That way, you can pick up (in theory) situations where Side Chain X rotates out of the way, which allows Water Molecule Y to be exposed and more easily be displaced as Ligand Z backs into the spot like someone learning to drive an 18-wheel truck, with plenty of halting and readjusting, etc.
But getting that to work is another thing entirely (as this and the comments sections to this older post will make clear). One problem is that if static modeling has its problems, what happens when you assemble frame after frame of static modeling into a movie? “That’s not what we’re doing” is the response from the MD people, but the point about errors possibly propagating through the simulation remains. The only way to do dynamics right (in my own view) is to throw a really ferocious amount of computing power at it, make as few simplifying assumptions as possible, and just calculate until you can’t stand it any more.
And that’s pretty much what Relay is up to. The company’s founders knew very well what they were up against, and recruited David Shaw’s organization to help out. Shaw, as mentioned above, led an extremely successful quantitative-trading company for many years, using computational methods to exploit small inefficiencies in the equity markets. But more recently, he’s been using his resources to fund D. E. Shaw Research, doing fundamental work in computational chemistry and biology with as much computing horsepower as can be obtained. (Here’s Shaw talking about that work in a lecture to the Biophysical Society). Even a few years ago, the hardware/software combination didn’t really exist to take on the long binding simulations that Relay’s founders wanted to go after, but that’s recently come into the realm of possibility. (Update: Mark Murcko of Relay (a longtime reader here) has left a comment pointing out that the company has plenty of experimentalists, structural biologists, etc., and that they’re far from a pure computational play. That’s true, of course – that 1981 story linked to above showing steely-eyed drug designers making drugs right off the screen is just as much of a dream now as it was back then).
And they seem to be getting somewhere. I’ve known some of the folks at Relay for years, but they’re not going to tell me any secrets (I work for the competition!) But it looks like they’re taking a lead molecule into the clinic next year if all goes well, and it’s my understanding that they’ve gotten where they are by using an unprecedented amount of computing power to guide their synthetic chemistry. I’m very interested to see where this leads. One the one hand, molecular dynamics, done right, could indeed provide insights that are both important and difficult-to-impossible to obtain any other way. On the other hand, though, done wrong, even slightly wrong, it could just be a very expensive way of making yourself believe that you’ve got a handle on things, even if you don’t. (I can assure you that Relay’s people are keenly aware of that danger, which is a good thing). And on the gripping hand, there’s always the chance that producing a good molecule using MD will just allow you to move a layer deeper and find the real problems with your therapeutic hypothesis, as so often happens in drug discovery. But that’s still progress.
From what I can see, other companies are taking a wait-and-see attitude towards all this, not least because “Use David Shaw’s custom-built supercomputer” is not a technique that scales well for now. But people are watching, and watching with interest, to see if this actually is the future.