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DBL%20Hendrix%20small.png College chemistry, 1983

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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« More Pfizer Layoffs? | Main | Happy Fourth of July »

July 3, 2008

I Can Has Ugly Molecules?

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Posted by Derek

A colleague and I were talking the other day about some of the molecules that turn up when you dig through a company's internal database. This was a favorite sport of mine during slow afternoons at the Wonder Drug Factory - I would put in a query for bizarre or unlikely chemical groups and see what fell out. I was rarely disappointed - eventually I assembled a folder of the most hideous examples, which never failed to astound.

The compound collection at my current employer isn't nearly so weird, fortunately. But every drug company has large lists of compounds that aren't so attractive as leads, because they were made in the last stages of previous projects. This is a well-known problem, often referred to as a gap between "drug-likeness" and "lead-likeness". For the most part, the compounds you start a project with don't get smaller - they get bigger, as people hang more things off of them to get more potency, selectivity, or what have you. So you're better off starting as small as you feasibly can, giving you room for this to occur without taking you off into the territory of too-huge-to-ever-work. (That's one of the fundamental ideas behind the vogue for fragment-based drug discovery, for example).

"Too-huge-to-work" is a real category, as my industry readers will gladly verify. I think that the "Rule of Five" cutoffs have been sometimes applied a little too mindlessly, but there's no getting around the fact that if your latest molecule weighs 750 and has thirteen nitrogen atoms in it, the odds of it being a drug are rather slim. As my colleague put it, when you make something like that and send it in for testing, what you're saying is "I know that almost every molecule that looks like this fails. But I'm different. I feel lucky". And that's no way to run a research program. Given finite time and finite money, you're better off prospecting in chemical areas with better chances.

So what to do? We kicked around the idea of setting up some filters in the compound registration system itself - if someone tries to send in some horrible battle cruiser of a molecule, the system would make a puking noise or something and refuse to register the compound at all. There would have to be be some sort of override (perhaps for a higher-level manager to authorize) for those times when you actually have evidence that the ugly molecule works, but maybe the "You Lose: Make Something Else" screen would focus attention on the properties of what's being made. Of course, if anyone ever implemented this, the arguing would begin about where to draw the line (maybe there'd be a yellow "warning zone" in between), but I think that everyone agrees that at some point a line should be drawn.

So, for my readers around the industry - do you have such a cutoff? Can you register any crazy compound that crosses your bench, or does your company's software fight back? If so, what's the feedback - beep, e-mail warning, electric shock? Inquiring minds want to know.

Comments (26) + TrackBacks (0) | Category: Life in the Drug Labs


1. burt on July 3, 2008 9:01 AM writes...

Fugliest of the week should get posted in the labs.

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2. Sili on July 3, 2008 9:16 AM writes...

Nothing to say since I'm not in industry (or employed for that matter), but now you've made me want to see some LOLecules macros.

Perhaps that would be the way to go re the naming and shaming burt suggests.

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3. SP on July 3, 2008 9:32 AM writes...

Not size, but here's an excluded functionality filter. Most of this is bloody obvious- no anhydrides in a screening deck? Really? What if I have a really good one?

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4. Honclbrif on July 3, 2008 10:13 AM writes...


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5. T on July 3, 2008 11:14 AM writes...

Shoot, does this mean that my series of polyfluorinated aziridines is going to regarded as suspect?

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6. Darth Bubbster on July 3, 2008 11:16 AM writes...

We've actually just instituted a registration-gate with somewhat relaxed Ro5 filters. I'm so curious to see what the filtration rate ends up being.

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7. Zza on July 3, 2008 11:35 AM writes...

Top this one: Osmium & Staurosporine

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8. excimer on July 3, 2008 11:43 AM writes...

We did a LOLnano contest a while back...

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9. industry guy on July 3, 2008 12:33 PM writes...

You wouldnt believe the fugly compounds of a project where im at. Its a joke...MW=850 anyone? lol.
But lets keep working on it disregarding it will take the entire scope of development resources to prepare it for trials...

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10. nils on July 3, 2008 12:39 PM writes...

We have such filters for external compound purchase. All vendor catalogues are filtered using some (rather soft) filters such as unwanted substructures and so on. Compounds that do not pass the filter are never shown to anyone.

It turned out very difficult to define such filters since there is a great fear to "loose the billion dollar compound". And there is always someone who once worked with compounds that contain a certain funcional group and were still okay. Really.

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11. Karen on July 3, 2008 12:57 PM writes...

At my first job, the first compound I ever worked on had a MW of over 1300. It was a natural product, so it wasn't your typical chemical structure, but still, it had great activity and it went a long way before the project was killed. (Its fate had more to do with commercial considerations than scientific ones.)

Working on that compound gave me a much broader idea of what a "good compound" looked like. I still put that compound on my research summary - people always look at it and goggle.

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12. Spike on July 3, 2008 1:16 PM writes...

We shouldn't forget that the Rule of Five was designed for orally administered drugs. Having a filter that would stop you from registering compounds that violate the RO5 (or other standard) would exclude you from registering some drugs that would be administered IV or are designed to act in the GI tract. That may be a high price to pay in order to only enusre that only the "beautiful" compounds are in the database.

As an example, AMD3100 doesn't look too pretty but works pretty darn well as an IV administered drug. There are many other examples that can be given.

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13. weirdo on July 3, 2008 1:41 PM writes...

Filters need to be project-driven, of course, so any sort of corporate filter is a bad idea.

Look at elesclomol. Yeah, I think the same thing. But Glaxo paid, what, $80 million plus downstream milestones and royalties for it.

And how many kinase inhibitors are out there with acrylates attached "in just the right spot" to induce irreversibility? Some of those are in Phase 2. (I'm not advocating that they SHOULD be, I'm just sayin' . . . )

Today's project teams have a lot of bias. But they also haven't been particularly successful. One wonders if the two go hand in hand.

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14. Green Koala on July 3, 2008 1:53 PM writes...

Had a compound progress into Phase IIB showing good properties and great efficacy. Got dropped due to mechanistic, not structure, issues. It had a MW~700 and 6 F's.

A number of outliers like this out there, but smaller is always better. The guidelines (not rules) are out there; just got to use them smartly.

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15. Hap on July 3, 2008 2:08 PM writes...

Natural products always seem like a place to get really ugly molecules - CC-1065 and calicheamicin for example look ugly enough to induce nightmares. Conjugated to antibodies, though, they work pretty well.

I think my concept of ugliness is different because I'm not a med chemist. To me, high strain or reactivity = ugly, but YMMV.

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16. Wavefunction on July 3, 2008 4:26 PM writes...

Some of the emerging compounds for inhibiting protein-protein interactions are rather large.

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17. chemdaddy on July 3, 2008 6:57 PM writes...

The rule of five should be amended to include: "if 5 chemists with 5 years of experience or more each think that the molecule in question is ugly....survey's ugly". The violating chemist in question should be spanked for every H-bond donor or 100MW beyond Lipinki's suggestions. Double spanking for nitros, polyindoles, and anything that chemdraw can't name.

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18. milkshake on July 3, 2008 7:30 PM writes...

The best filter realy is a your difficult boss. Once gets quckly discouraged by incredulous response "You are making - what? Is this some kind of joke?"

I once made + submitted a compound substituted with THREE cyclopropene rings and each of them ringz had three amino substituents sprouting of them. But I swear, your honor, it was an accident.

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19. psi*psi on July 3, 2008 9:43 PM writes...

I agree with #2--we need to see some LOLecules!

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20. vasili on July 4, 2008 7:22 AM writes...

Derek, which company is the Wonder Drug Factory?

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21. Anonymous on July 4, 2008 7:45 AM writes...

I can one-up you. At my first job in the early nineties, working for a small therepeutic-area focused site of a large multinational, we had a rudimentary database, but our compound collection (100-150k compounds going back to the 50's) was open, and was right next to the graveyard for reagents purchased from e.g. Aldrich. You could kind of find something in the database, and you could kind of request it be delivered to you or to screening, but much more productive to go and get it yourself. Also, you got to scrounge through the old bottles and see who had made what - the structures were hand-drawn (or sometimes dwawn with templates :P) on the bottles.

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22. Norepi on July 4, 2008 10:02 AM writes...

LOL @ #17.

The filters for my project tend to exclude more on the basis of functional groups (a la # 3). Around here, they really like to get people for anything that they even *think* will act as an alkylating agent, even if it's as non-electrophilic as you can imagine. Alkyl chloride? DO NOT WANT. Also, the usual reactive beasties: epoxides, azo-whatzits, nitro-whatever, Michael acceptors, and soforth. They also hate PEGylation, polyhydroxylation, wacko conjugates, bis-pharmacophores, and just about every other gimmick you can think of.

They don't especially care about size, as many of my compounds are >300/400, but they're not especially gross Ro5 violators...

And quite often, they pitch compounds simply because they think the molecules are "too similar" (eg, imidazole vs pyrrolidinol). Drives the lab head up the wall.

Happy 4th to everyone, and especially to you, Derek.

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23. u. sam on July 4, 2008 1:25 PM writes...

#20: Bayer

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24. Canuck Chemist on July 4, 2008 1:32 PM writes...

Chemdaddy: Just curious...what's wrong with polyindoles (I'm working on some bisindoles linked in various ways)?


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25. Polymer Bound on July 4, 2008 3:31 PM writes...

We don't have a registration filter in my shop, but the folks who run the compound collection make sure that only good compounds get into the HTS screening set using a number of different filters (and quality control). There are still tons of chemical oddities in there from decades ago and weeding them out is an ongoing process.

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26. lemieux66 on August 6, 2008 8:50 PM writes...

When I was at Rhone-Poulenc-Rorer back in the late '90s, they had a Lipinski program linked to the compound submission program, so that you could prescreen your compound (before you made it-so that you might want to tweek it if you could). The guy who programmed it was a BIG Clint Easwood fan, because, if it failed more than 2 criteria, a picture of Eli Wallach (The Ugly, in The Good The Bad and The Ugly) would pop up on your computer screen. Always funny to see.

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