There’s an article in the latest Drug Discovery Today which takes off after the “Rule of Five” and its application to drug discovery. The author’s not saying anything that hasn’t been said before, though – first under the breath, then openly. But it bears repeating:
”The simplicity of these criteria to remove outlier molecules using software, made them very easy to implement. Thus, the Ro5 moved rapidly in the hierarchy of medicinal chemistry concepts from being a set of ‘alerting’ criteria in the minds of the medicinal chemists to a commandment engraved in the high altars of ‘do's’ and ‘don’ts’ of drug seekers. I am not a medical doctor nor am I a savvy drug-discoverer; I am just an apprentice. However, I suggest that ten years after the publication of the Ro5, it might be time for a collective reflection.
Currently, the Ro5 is used almost indiscriminately. I think that we should be very cautious about relying too heavily on these criteria, for two reasons. First, it is worth pointing out that there are examples of successful drugs (i.e. Lipitor™, Atorvastatin™) that are notable violators of the Ro5 and we and others should never underestimate the impact of the highly improbable event in our theories and preconceived notions. Second, it is well recognized in the drug discovery field that in spite of these magic rules, and the introduction of ingenious methods to discover new drugs, the number of new chemical entities reaching the market has remained constant or continued on a downward trend. One may ask: Where is the power of those magic rules? Are they helping us to focus on the right molecules? Or are they preventing us from discovering new opportunities? Do they represent something deep and profound about drug discovery? Or are they preventing us from a deeper understanding of the drug discovery variables?”
The problem is, this sort of article is coming along several years too late. I disagree with the word “indiscriminately”, for one thing. It’s actually my impression that Rule-of-Five dogmatism has been on the wane for a while now. I’d put the peak at about five to eight years ago, myself (anyone out there have the same experience?) Perhaps it’s the lack of any strongly noticeable increase in our success rates that’s calmed things down. Projects are still wiping out due to odd and unexpected pharmacokinetic problems, for example, where the more naïve (or hopeful) devotees of the rules might have looked for an improvement. (This would be a good place to note that Chris Lipinski himself never was as hard-core about his criteria as some of his followers, a pattern which is far from unknown).
So it’s clear that success can’t be ensured by just matching a few basic properties of drugs that have been successful in the past, not that this should be a surprise. People are always looking for the easy fix (who can blame them?). The Lipinski rules were a favorite among middle management, more than for the people at the bench, since they used measurable criteria to produce something else that could itself be measured. Nothing is dearer to a manager’s heart, and it’s too bad that the results haven’t been more exciting.
I liked better an analogy made later in the paper:
”I see the historical successes of our illustrious predecessors more like the discoveries of early sky watchers. They discovered the early stars and planets and through careful observations were able to trace their passages through the sky. Like them, we have discovered certain patterns in the firmament of drug discovery as they relate to various chemical entities with therapeutic properties, and characterized the molecules in the biological universe to which they relate. However, I would not go any further than that. In trying to understand the universe of drug discovery, I am not even ready to affirm whether we know with certainty if the system is geocentric (ligand at the center, as it would be suggested by medicinal chemists) or heliocentric (target in the center as proposed by biologist, macromolecular crystallographers or geneticists). Moreover, although we have a sense of what the forces that bring the two together are, robust calculations that can accurately predict how one relates to the other still elude us. We know there is a key parameter (i.e. Ki, their relative affinity) that connects this crucial pair but we cannot calculate it accurately. Consequently, the number of experimental observations (in vitro and in vivo) relating the two dominant poles of the drug-discovery universe is extensive and continues to grow in the existing databases (public and proprietary) at an exponential rate. All these measurements remind me of the careful observations made by Tycho Brahe (circa 1600) that were crucial for Kepler's insights.”
He’s right that in medicinal chemistry we’re still fundamentally an observational science. (That should have been obvious given how little math any of us need to know). We have broad theories, trends, rules of thumb – but none of it is enough to help us very much, and we’re constantly surprised by our data. That can be enjoyable, if you have the right personality type, but it sure isn’t restful, and a lot of the time it isn’t very profitable, either.
And as an amateur astronomer, I like the analogy, although it worries me a bit. Kepler (and Newton) did indeed break the impasse over the motion of the planets by explaining the available data through relatively simple (but still unexpected and non-obvious) mathematical theories. We’re not going to be so lucky, since the systems we’re studying are so much messier and subject to so many more influences. But there is room for some sense to be made out of what we’ve observed, more sense than we’ve made of it thus far, at any rate.
Understanding is not going to come down on us like a descent of holy fire, which must have been what the laws of gravity and planetary motion were like, but it won’t have to. I’m not expecting an airtight theoretical approach to predicting human blood levels or toxicity, not anytime soon. But considering that we lose amazing amounts of money because we can't predict that stuff at all, I think we're actually going to be pretty easy to impress.