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Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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November 27, 2007

Then I Felt Like Some Watcher of the Skies. . .

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Posted by Derek

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.

Comments (16) + TrackBacks (0) | Category: Drug Development | Drug Industry History


1. Grubbs the cat on November 28, 2007 3:19 AM writes...

I was never happy with the terminus '_Rule_ of five'. Whenever I refer to them, I use 'Lipinski guidelines' instead.

I think that 'rules' have the stigma of being set in stone. If there is a rule, you have to argue when you are breaking it (can be difficult in discussions with non-medchemists e.g. biologists)...

...on the other hand - is it not our duty as scientists to break the rules ;)

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2. Petros on November 28, 2007 3:20 AM writes...

Unfortunately I can't read the full article, since I ddin't renew mu sub to DDT (I used to get it for free)!

I think the Rule of 5 has to be seen in the context of when it was devised. The advent of HTS put the pressure on chemistry to deliver lots of compounds amd prompted most companies to adopt sledghammer combinatorial approaches churning out large numbes of compounds that were highly R o % non -compliant. And those were supposed to provide leads not canidates!

And while there are succesful exceptions like Lipitor, just think back to all the renin inhibitors that failed in the 1980s and early 90's when most companies were working on them. The lwoest molecualr weight inhibitors teended to be ca 650 Da. And none of those got to the market!

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3. Eraser on November 28, 2007 3:58 AM writes...

This does bring to mind what Captain Barbossa said in the first Pirates of the Caribbeans movie:

"They're more like guidelines than actual rules."

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4. PG on November 28, 2007 4:35 AM writes...

There is an interesting review this month on the subject of drug-likeness by some folks from AstraZeneca (Nat Rev Drug Discovery, vol 6, p881), looking at the physical properties of drugs that made it through to the market, and arguying that a much greater emphasis should be put on lipophilicity.

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5. Kay on November 28, 2007 6:59 AM writes...

Many in pharma are simply punching the clock. A strongly-worded article might just help them to cause less damage to their employer. Junk science is not easily forgotten by the clock punchers.

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6. SP on November 28, 2007 8:40 AM writes...

Lipinski is definitely a geocentric guy- his favorite topic of the moment is phenotypic screens. Forget about the target, feed what you've got to the cells/mice/rats/dogs and see if you like what happens.

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7. John Spevacek on November 28, 2007 9:26 AM writes...

As has been said elsewhere, "Half the fun in chemistry is discovering the rules, the other two-thirds of the fun is in breaking them. Physicists are better mathematicians and therefore have 16.7% less fun."

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8. Ralph (ZZ) on November 28, 2007 11:12 AM writes...

If you liked that, you'll like this one from Nature Reviews Drug Discovery.

"The influence of drug-like concepts on decision-making in medicinal chemistry"

"The application of guidelines linked to the concept of drug-likeness, such as the 'rule of five', has gained wide acceptance as an approach to reduce attrition in drug discovery and development. However, despite this acceptance, analysis of recent trends reveals that the physical properties of molecules that are currently being synthesized in leading drug discovery companies differ significantly from those of recently discovered oral drugs and compounds in clinical development. The consequences of the marked increase in lipophilicity — the most important drug-like physical property — include a greater likelihood of lack of selectivity and attrition in drug development. Tackling the threat of compound-related toxicological attrition needs to move to the mainstream of medicinal chemistry decision-making."

The paper takes a look at Lipinsky rules over the years and withing different organizations and notices a few broad trends of divergence over time among approved drugs(confirming Dereks intuition).

Good read - and freely accessible (may need to register with Nature).

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9. pa on November 28, 2007 2:54 PM writes...

Like many other simple models, as the Ro5 gained wider acceptance, arguably more and more of the understanding of the model limitations are forgotten. In addition, one of the curses/blessing of the Ro5 is that it is quantified. This is a double-whamy. Many conversations find an abrupt end once the Ro5 numbers are brought in. While numbers can be useful, they are only useful when an error margin is provided. Too many times, people forget the error margins and hide behind the predicted numbers to justify their position on the merits of such and such compound.

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10. Great Molecular Crapshoot on November 28, 2007 5:02 PM writes...

The Rule of 5 is based on analysis of property distributions in a database of oral drugs. The cutoffs specified by the rule are typically set so that 10% of the drugs exceed the cut-off. Managers love Ro5 because it's so easy to apply and the connection to oral bioavailability is simply nice to have in this context. There are some Ro5-related posts on the Crapshoot and these have been indexed.

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11. SBC123 on November 28, 2007 5:16 PM writes...

RO5 was derived based on an analysis of phase 2 and beyond compounds, but the background was not considered. 90% of the phase 2 compounds have MW

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12. SBC123 on November 28, 2007 5:21 PM writes...

Well my question was cut short. I was wondering what if 90% or more of the compounds did not make to phase 2 also have MW

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13. Brooks Moses on November 29, 2007 12:33 AM writes...

SBC123: Let me guess -- the rest of your comment started off with < something, and went on from there. And that of course gets interpreted as an unclosed HTML tag....

The trick is to write your < as "&lt;". Or as "less than".

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14. SBC123 on November 29, 2007 9:24 AM writes...

Brooks Moses: Thank you. Now I can finish my question. MW less than 500 being a positive attibute to drug likeness is based on the assumption that less than 90% of all compounds screened have MW less than 500 (same is true for HD, HA, clogP). What if 90% or more of the compounds did not make to phase 2 also have MW less than 500 (it is unlikely but we do not seem to have this information). That would imply MW less than 500 may be a negative attribute. There appeared a flaw in Lipinski's argument to me. Am I missing something here? I think Mark Wenlock's study is more convincing.

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15. Great Molecular Crapshoot on November 29, 2007 2:47 PM writes...

In response to sbc123,the ro5 analysis is indeed based on property distributions of phase 2 compounds and minimal reference was made to non-phase 2 compounds. The Wenlock study is indeed more convincing.

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16. TX Raven on December 7, 2007 5:32 AM writes...

After working for 13 years in CNS drug discovery, I feel like an apprentice too. Isn't that the fun part?
While it is true that for CNS drugs small seems to work better, a negative impact of the Ro5 is to make us think that following a small number of unjustifiable rules will increase your likelihood of taking a drug to the market at the expense of THINKING about what you are doing and what the data is telling you.
I know: the Ro5 and the thinking were not supposed to be incompatible, right? Well... apparently experience shows they are...

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