Here’s a good blog post with a lot of food for thought, and here’s the follow-up. I missed these back when they came out last year, but the issues they raise are (for better or worse) evergreen. The author’s framing a debate about medicinal chemistry as Cavaliers-versus-Roundheads, which is a classification that’s useful enough to have been applied ever since its origin in the English Civil War. Over time (and in these two posts), it’s come to mean making a distinction between a more Puritan outlook, people who are sticking to principles (especially principles about what shouldn’t be done), and a more laissez-faire pragmatic view:
. . .I am sure that those more historically literate than myself will highlight why this is a bad analogy. Its also very UK-centric for which I apologise for indulging myself. However, I think it is a useful comparator to explain what I think is wrong with many of the bandwagons that go zooming by if you just wait around long enough in a drug discovery environment. Its not so much the roundheads as having a distinctive look or political grouping that is the source of the analogy I wish to draw but their puritan roots. In particular, it is the puritan tendency to tell people what they should NOT do and their propensity for banning things which is the basis of the comparison I want to make. Notably, they undid themselves by (amongst other things) banning things such as the various feasts and festivities and the vividly decorated public buildings that were some of the few sources of gaiety for many of the populace.
The comparator that I wish to make and which therefore, I think makes me a cavalier, is that there are too many people trying to tell drug discoverers what NOT to do but without providing any particularly useful guide to what they should do instead. I further speculate that, like the roundheads, this approach is wont to sap the joy out of drug discovery for many and ultimately is unlikely to spur the kind of creativity that we cavaliers think essential for success in this field.
Historically, there is a problem with this definition creep, because (among other things) the Cavaliers were fighting (with all the means at their disposal) for the divine right of kings, which doesn’t sound all that open and creative to modern ears. (It’s also worth keeping in mind that the Puritans themselves were only a minority of the Roundhead supporters, most of whom were still Church of England). But I’ll leave the history aside, because it is a side issue here, and go to the main point of the argument.
The author very much objects to things like up-front assessments of compound tractability, target druggability, and so on. I feel his pain, actually:
It has frequently shocked me to hear medicinal chemists pontificating about what will and will not work. It has too often felt like a delusion. Actually, that’s not quite right. In terms of stacking the odds in your favour, it is a pretty good idea to say that everything will not work. This makes medicinal chemistry ideal territory for self-satisfied Roundheads. But how unhelpful, how uninspiring. In an environment in which little is understood definitively, we require persistent sorts who can take the knocks of things not working as hoped and can pick themselves up and do it all again. A corrosive presence that will decrease the prospects of success is the one who can only tell you why they think something will not work or worse, the “told you so” sorts who don’t even make testable predictions.
In fact, I’ve said very similar stuff myself, to the effect that you can sit in the back of the conference room and say over and over that things won’t work, and in this business you’ll be right almost all the time. But to what end? It’s the small residuum of things that work that we really care about. So I know where the objections to the “Don’t make this, don’t do that” sort of rules are coming from, because it seems as if you’re setting yourself up for failure after failure, while all the time assuring yourself that you’re doing the right thing for the right reasons. It can be infuriating to listen to, and infuriating to watch.
But that said, I think that there’s a bit of a false dichotomy here. Both sides of these arguments about compound metrics, undruggable targets, intractional PAINs and so on can be taken to reducio ad absurdum extremes. In fact, here they are: on one side, you could say that there are long lists of targets that should never be attempted, huge swaths of compounds that should never be made, and piles of screening hits that should immediately be purged, to the point that there’s little left to work on at all. And on the other, you would have people who are more than ready to let a thousand flowers bloom, to work on whatever, however, because you never know what might turn up or work out well in the end.
Both of these, though, are caricatures – or I hope that they are. Try some thought experiments: if you’re a hard-core rule-of-fiver, then you have excluded some of the most useful drugs in the entire pharmacopeia. You never would have made their structures, you never would have followed up on them as hits if you’d seen their structures at the beginning, and the more fool you for doing so. Similarly, if you have very firm ideas about target druggability, you probably would not have believed a priori that there could be drugs targeting microtubules, FKBP, or the protein synthesis initiation complex. But there are wildly useful drugs that hit all of these, and plenty of equally wild targets as well.
On the other side, though, if you’re OK with going to a 500 MW compound and optimizing it, because all this rule-of-five stuff is an artificial construct, then how about 600? 850? 1405? Synthetic difficulty aside, you really do start to run into some practical problems dosing these things in living creatures. And if you were, say, to run into a situation where you could treat Disease X by either making a Type I GPCR antagonist or by (say) targeting an intrinsically disordered nuclear receptor cofactor protein in the CNS. If you had no reason to think that (from a disease-modifying perspective) one of these was any better than the other, would it still be just a coin flip to decide what to put tens of millions of dollars and years of your life to working on?
Well, these examples are caricatures, too, but that’s what a reducio ad absurdum does – show you that there is indeed some absurdity waiting out there for you.The important thing, I think, is to have a sliding scale in your mind for all these factors, and to understand the risk/reward for each of them. Some targets really are more tractable than others, even if there’s a giant middle of the scale where these distinctions are difficult or impossible to make. And some compounds really do have a better chance of becoming drugs than others, although there are no clearly makred electric fences out in that territory, either. If your target is a class of interaction that no one’s ever gotten to work before, you might not want to pile any more risk onto it in other categories if you can help it. If your chemical matter is really outside the experience of everyone you show it to, you’d better have a good reason for going there, and be ready to do extra tox, scale-up, and formulation work to get it to fly.
And even behind understanding the risk/reward level for each of these is the realization that there is such a tradeoff to be made, every time. I think Chris Lipinski was appalled at some of the uses that his rule of 5 paper was put to, because it was mainly just to show that marketed drugs tended to fall into certain areas of chemical space, which suggested that moving outside of them might well be associated, eventually, with a higher risk of not having a marketed drug. It’s human nature, I suppose, to take this sort of thing and run with it, and it’s certainly true that there is a particular personality that is likely not only to run with it, but start beating everyone else over the head with it when they arrive. That’s the Roundhead of the blog posts referenced above, and I can see where the irritation comes from.
But I can’t go all the way over to the other side, either – as I’m fond of saying, just because you can screw up in one direction doesn’t mean that you can’t ever screw up in the opposite one. There are ditches on both sides of the road. I think that medicinal chemists should indeed be creative, and had better be creative, because I fear that too many of the drugs that can be discovered by only doing what we know how to do have already been discovered by now. At the same time, though, “because it’s creative” isn’t enough of an argument in medicinal chemistry, either. It would be very creative of me indeed to fill a hundred-thousand-member screening library with nothing but quinones, because I’m sure that no one has thought of doing that before. I’ll get mondo honking piles of screening hits out of that set, too, no matter what I run through it. But ars longa, vita brevis, and I could easily spend the rest of my life and my next one, assuming I don’t come back as a sea otter or a crested grebe, trying to get one of these things to actually become a drug that might do someone, anyone, any good.