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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: derekb.lowe@gmail.com Twitter: Dereklowe

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August 26, 2011

Design a Molecule, Win an IPad (Which is More Than You Usually Get)

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Posted by Derek

For those of you who are (or have always wanting to try being) molecular modelers, Cresset Design is holding a contest you might enjoy. They're putting up a molecule and giving out temporary licenses to their modeling software, and inviting people to come up with the closest bioisosteric match. The winner gets a free IPad2.

Of course, you're not going to be able to win by suggesting a para-fluoro group or by making a tetrazole-for-carboxylate switch. In their words:

We will use the Field alignment score for your molecule to the reference molecule as the primary judgment in designing the winner. However, molecules with high 2D similarity or high calculated logP with receive a penalty and are unlikely to win. Also entries with reasonable chemistry and good synthetic feasibility will be favoured. Feedback showing the score for your molecule and describing which properties of the molecule are being penalised will be provided on request. The winner will be the molecule that, in the opinion of the judges, represents the best design chosen from the top scoring results.

Fair enough, I'd say. I look forward to a follow-up from them at the end of the contest; I'd like to see what sort of stuff comes in.

Comments (18) + TrackBacks (0) | Category: In Silico


COMMENTS

1. RD on August 26, 2011 10:32 AM writes...

Hey, thanks for the heads up! I'd rather have a job but this will keep me busy for awhile and I get to try new stuff.

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2. Boston on August 26, 2011 11:30 AM writes...

The future of chemistry is you'll live in a steel shack out back the company and if you design a life saving drug you'll get a meal.

Design two life saving drugs and you'll get a real egg breakfast.

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3. MoMo on August 26, 2011 12:21 PM writes...

An iPad for creating a drug that could bring in billions while paying the managers hundreds of thousands per year and with cheap stock options? Sounds like a great deal! Sign me up, Coach!

You got to get up pretty early in the morning to fool some of us chemists, and I could use an iPad!

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4. A Nonny Mouse on August 26, 2011 12:34 PM writes...

Ah, Andy Vintner- remember him from when I started in med chem and he was playing about with his green screens and touch pens to do 2-D structures. Changed a bit since then!

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5. Chris Swain on August 27, 2011 3:58 AM writes...

As a past winner I might be biased but I have to say I find these quite entertaining. Think of it as sudoku for chemists with the very, very tiny chance that it might generate a new lead for treatment of a third world disease.

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6. Pete on August 27, 2011 12:32 PM writes...

If the objective is an inhibitor of the parasite enzyme that is selective with respect to the human enzyme, I’m not sure that field fit against the bound ligand of the human enzyme is the best criterion to judge entries. The sulfonamide portion of the ligand in the 3E32 structure looks really strained and this is precisely the kind of situation in which I’d want to take a really close look at the electron density and have a chat with the crystallographer. It’s also the kind of situation in which I’d be anticipating differences in binding modes (including bioactive conformation) to the human and parasite enzymes.

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7. Demosthenes on August 28, 2011 9:36 AM writes...

Pete,

Don't be such a jerk. The contest organizers specifically said that the objective was to come up with bioisosteres that are synthetically tractable, nonsimilar, and have a reasonable logP.

Obviously, they intend to get more people interested in their tools so they can make money by showcasing how it can be used to design non-trivial isosteres of known compounds.

Quit moving the goalposts. Their method is designed to solve problem X. Don't get hypercritical because it doesn't address problem Y, which it wasn't designed to solve.

Permalink to Comment

8. Pete on August 28, 2011 5:24 PM writes...

Demosthenes,

I would suggest that you familarise youself with the concept of conformational strain and take a close look at the information associated with the PDB refcode 3E32 before calling anyone a jerk.

Here's what the Cresset people had to say:

"Our next challenge will be another anti-malarial target, a farnesyl transferase inhibitor which is a 1000 fold selective for plasmodium falciparum and the available X-ray structure of this compound bound to the Human form from PDB: 3E32"

I checked the refcode and associated publication. The species listed for 3E32 is Rattus Norvegicus and the selectivity stated in the publication for this compound is 112 (i.e. not 1000).

As I mentioned earlier the sulfonamide portion of the inhibitor appears strained. Given the selectivity of the inhibition, this observation brings into question the use of the conformation of the ligand bound to the human enzyme as starting point for design of inhibitors of the parasite enzyme.

As for the goalposts that you accuse me of moving, I don't think that they were placed with particularly great precision in the first place.

Generally science is about asking good questions. One reason that Pharma is so very much dans la merde is that research managers really would prefer that people not ask questions. If challenging and questioning makes me a hypercritical jerk then I'm proud to labelled in this manner.

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9. Demosthenes on August 28, 2011 7:22 PM writes...

Pete,

On the contrary, it is attitudes like yours that represent what's wrong with pharma. In other words, the "That won't work, so let's not even bother trying." I've gotten sick and tired of chemists routinely claiming that nothing ever works except med chem and nothing can ever be predicted, so the only way to discover drugs is to make compounds at random. You've witnessed the results of that approach for the last twenty years. How's it working out for you?

For your information, I do have a background in crystallography. Yes, it is indeed a strained system. If you had bothered to look more closely, you would realize that Cresset gives the user enough controls that you can control the minimizations, thus enforcing particular conformations if you so choose. Or, had it not occurred to you after reading the challenge that the entire purpose of the exercise might be to identify a novel core that isn't so strained but retains the key interactions in the proper locations?

The problem with science is that there aren't enough people willing to actually do hypothesis testing.

As for moving the goalposts, my comment stands. The goal of the challenge was straightforward, clearly stated, and limited in scope by the organizers. Your criticism is a classic one by chemists in pharma. If every compound you design doesn't solve all of the program's problems and isn't ready to go into the clinic, then there's no point in making it. They are looking for a replacement core, not a drug. Quit worrying about step Z when you're stuck on step A.

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10. xray prof on August 28, 2011 7:30 PM writes...

Pete,

Good catch. I just looked at the electron density maps for 3E32. The tail end of the molecule, from sulfonamide to phenyl, is definitely built incorrectly.

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11. BariTony on August 28, 2011 8:00 PM writes...

Pete, xray prof,

There's an easier way to tell this molecule is highly strained. By taking the reference molecule Cresset provides, minimizing it and hitting 'Process', per their recommended workflow, the resulting minimized and aligned conformer has a similarity score of 0.664. Pretty curious, given that the similarity score for the query is 0.848. I would submit to you that this design competition is a losing proposition, since even the reference compound is so far from the probe. On the other hand, if you choose to compete, that gives you an estimate of the maximum score you might be able to achieve for a designed compound.

Permalink to Comment

12. Pete on August 28, 2011 10:17 PM writes...

xray prof,

Thanks for checking this out.

Permalink to Comment

13. Pete on August 28, 2011 10:47 PM writes...

Demosthenes,

While I'm happy for you to call me a jerk and accuse me of being hypercritical, I don't see how my challenge to this exercise means that my attitude is "That won't work, so let's not even bother trying".

My point was simply that the apparently strained nature of the ligand bound to rat enzyme raised concerns about its suitability as a probe for biostere-based design of inhibitors of the parasite enyzyme given that the compound is 112-fold selective in favor of the latter. I didn't see an IC50 value for inhibition of the rat enzyme and to be quite honest this is another piece of information that would be very relevant to this discussion. If you are offended by people asking relevant questions then perhaps you should never have got into science in the first place.

If the conformation of a bound ligand is indeed strained then this usually represents an excellent design opportunity. Similar considerations apply when proteins bind tautomers and ionisation states that are relatively high in energy. Here's an example of how a fragment was locked into its bound conformation: Demosthenes,

While I'm happy for you to call me a jerk and accuse me of being hypercritical, I don't see how my challenge to this exercise means that my attitude is "That won't work, so let's not even bother trying".

My point was simply that the apparently strained nature of the ligand bound to rat enzyme raised concerns about its suitability as a probe for biostere-based design of inhibitors of the parasite enyzyme given that the compound is 112-fold selective in favor of the latter. I didn't see an IC50 value for inhibition of the rat enzyme and to be quite honest this is another piece of information that would be very relevant to this discussion. If you are offended by people asking relevant questions then perhaps you should never have got into science in the first place.

If the conformation of a bound ligand is indeed strained then this usually represents an excellent design opportunity. Similar considerations apply when proteins bind tautomers and ionisation states that are relatively high in energy. Here's an example of how a fragment was locked into its bound conformation (sorry for not posting the doi but it looks like I'm not allowed to do that):

BMCL 2005, 15, 2503-2507



Permalink to Comment

14. Pete on August 28, 2011 10:53 PM writes...

Having another go at posting the doi for the BMCL article:

dx.doi.org(slash)10.1016(slash)j.bmcl.2005.03.068

Permalink to Comment

15. Ryan K. on August 29, 2011 4:31 AM writes...


Just for the record, the IC50 values are 25nM in the Norwegian Brown Rat, and 56nM in Homo Sapiens.

http://www.bindingdb.org/jsp/dbsearch/PrimarySearch_pdbids.jsp?pdbids_submit=Search&pdbids=3E32

Permalink to Comment

16. Demosthenes on August 29, 2011 7:24 AM writes...

Pete,

OK, I was out of line calling you a jerk. You are right that the ligand is highly strained. (I can't view electron density maps these days, so thanks xray prof for checking this out.)

Still, I think you're over-thinking the problem. If the objective is a selective inhibitor for a clinical candidate then yes, selectivity is a relevant issue. But it's not in this case. The very small contest they've proposed says nothing to do with designing a selective inhibitor. They're a software company, so I don't even think they're interested in drug development.

I've competed in other contests like this before. The 'winning' result ends up looking like something that wouldn't be used in real life. Their criteria are their similarity score (which may or may not be relevant or even good, but that's another ball of wax), similarity, and logP. Worry about selectivity and other factors all you like, but if that's how they're judging the competition it's not going to matter. That's why I argue the selectivity issue isn't relevant in this case. It's easier to design a winning compound that meets these criteria than to design a clinical candidate.

Permalink to Comment

17. Pete on August 29, 2011 8:45 AM writes...

I didn't see a rat IC50 given in the paper although I was reading off the screen and so may have missed it. The human value is listed in Table 1 as 56nM plus/minus 29nM. I am concerned about the coincidence between the lower limit of the confidence interval for the reported human IC50 and the value of the rat IC50 in the bindingdb. I'm not sure how IC50 values get into the bindingdb and if anybody associated with that database is following this discussion then they might want to take a closer look at these database entries.

Permalink to Comment

18. bioc on September 10, 2011 2:59 PM writes...

Pete, xray prof,

Interesting points. One of the great things about this blog is the well-informed comments.

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