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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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February 28, 2012

More on the NIH's Molecular Libraries Program

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Posted by Derek

I last wrote about the Molecular Libraries program here, as it was threatened with funding cuts. Now there's a good roundup of opinion on it here, at the SLAS. The author has looked over the thoughts of the readership here, and also heard from several other relevant figures. Chris Lipinski echoes what several commenters here had to say:

Lipinski notes that when the screening library collection began the NIH had little medicinal chemistry experience. "I was a member of an early teleconference to discuss what types of compounds should be acquired by the NIH for high-throughput screening (HTS) to discover chemical biology tools and probes. Our teleconference group was about evenly split between industry people and academics. The academics talked about innovation, thinking out of the box, maximum chemical diversity and not being limited by preconceived rules and filters. The industry people talked about pragmatism, the lessons learned and about worthless compounds that could appear active in HTS screens. The NIH was faced with two irreconcilable viewpoints. They had to pick one and they chose the academic viewpoint."

He says that they later moved away from this, with more success, but implies that quite a bit of time was lost before this happened. Now, we waste plenty of time and money in the drug industry, so I have no standing to get upset with the NIH about blind alleys, in principle. But having them waste time and money specifically on something that the drug industry could have warned them off of is another thing.

In the end, opinions divide (pretty much as you'd guess) on the worth of the whole initiative. As that link shows, its director believes it to have been a great success, while others give it more mixed reviews. Its worth has surely grown with time, though, as some earlier mistakes were corrected, and that's what seems to be worrying people: that the plug is getting pulled just when things were becoming more useful. It seems certain that several of the screening centers will not survive in the current funding environment. And what happens to their compounds then?

Comments (11) + TrackBacks (0) | Category: Academia (vs. Industry) | Drug Assays


1. jtd7 on February 28, 2012 9:54 AM writes...

" . . . waste time and money specifically on something that the drug industry could have warned them off of . . . " You can be stronger here. According to Lipinski's account, they wasted time and money on something representatives of the drug industry DID warn them of.

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2. anon the II on February 28, 2012 11:52 AM writes...

That's interesting. Four of the eight people pictured in the article were associated with Sphinx and Lilly. They range from it's founding as a protein kinase C company to it's development as a high-throughput screening facility to it's final destruction; in order of appearance.

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3. Tom Womack on February 28, 2012 1:08 PM writes...

I'm not sure that the viewpoints are necessarily irreconcilable; I can certainly see an argument of the form 'we used these rules to narrow down the compound sets back when screening was extremely expensive; if it's now ten times cheaper then it might be worth putting in more of the historically low-real-positive families'.

For example, if the NIH work has resulted in documents in the open literature disclosing success rates within compound families which were common knowledge within drug companies but closely held as a competitive advantage, I would say it had done a good thing.

I don't know how the NIH's robot work at compares to commercial robots or to big-pharma HTS facilities.

On the other hand the project does seem to have managed the classic big-project failure mode of building expensive infrastructure for which the substantial running costs turn out unavailable in the future. I just hope that pubchem will carry on even if some physical labs have to be shuttered.

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4. anonymous MLPCN chemist on February 29, 2012 10:46 AM writes...

I work on molecular libraries probe development projects every day. We use Lipinski and other filters, Pfizer "structure alerts" criteria, and plain old medicinal /pharmaceutical chemistry common sense to prioritize the compounds and scaffolds we work on and develop into chemical probes. We have to: the NIH library has a lot of junky compounds that light up >10% of the screens they see (quinones, thiazoline diones, Michael acceptors, alkylators, fluorescent compounds, biotin analogs, etc). IMO we all know enough to ignore them, even if they are at the top of "most potent compounds" list from HTS.

The program aims to make publicly available potent and selective compounds that are the first small molecules to act at a certain new target or that act by a previously unknown/untested mechanism deemed exciting by peer review, and to share the data. It is a worthwhile objective.

The "molecular probe" that emerges isn't supposed to be a drug, but obviously if it is more drug-like it will be used more by biologists and pharmacologists exploring the importance of the target or pathway in question. We check for solubility, CYP inhibition, stability to liver enzymes, do broad target activity profiling, etc. and (if the NIH wants) we do full animal PK as well. I'd prefer to do animal PK every time, frankly, but some screening centers can't do it.

My feeling is that a lot of people seem to underestimate the amount of work that goes into NIH probe development and seem to think that there is no attention whatsoever paid to pharmaceutical properties of the compounds being studied. This could not be further from the truth.

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5. Fries With That? on February 29, 2012 2:27 PM writes...

I'm sure those libraries from the foreclosed screening centers will be swooped up and hustled away by third parties, for free, essentially. That's what happened to Celera's library.

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6. Molecules for For the People on February 29, 2012 3:19 PM writes...

If all of these compounds were made with taxpayer money they should be available to all who would like to screen them, provided they have the ability to do so.

Sure there are compounds that would make Lipinski cringe, but they are the property of the United States, paid for by Taxpayers, and they should be treated as national resources, not as wards of select "Centers" that control them or allow them to languish.

These molecules should be protected by an American based company that can watch over them properly.

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7. CR on February 29, 2012 4:18 PM writes...

To Fries With That? and Molecules for For (sic) the People:

Most of the compounds in the screening library were purchased, not made. The compounds are housed with DPI/Evotec in SF. Each screening center was given a "copy"; but the actual library is housed and maintained at DPI/Evotec. Anyone can write a grant (and if funded) have a screen run at one of the screening centers and medicinal chemistry performed. All probes that come out of the MLPCN are available (free of charge) to any researcher that requests them - usually 5 - 10 mg, but can be in the gram range also.

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8. JB on February 29, 2012 5:40 PM writes...

To echo that (no liquid handling pun intended): the only thing that would be lost is some of the intermediate analogs at the centers. Each probe plus 5 analogs in the series is deposited to Evotec (20mg) for public use. The library itself is at Evotec and management of it is moving over to NCATS so it will still be a public resource, for whatever that's worth- 85-90% of it is from commercial vendors, only about 30k is "novel."
I'm also mystified by Lipinski's comment- why are innovation and diversity "irreconcilable" with previously defined filters?

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9. CR on February 29, 2012 7:50 PM writes...

Correct, the probe (20 mg) and 5 analogs are deposited with Evotec.

I still not sure why LipInski is still asked to give an opinion. Yes, we get it. We know the 'rules' and they shouldn't be dogma.

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10. anon2 on March 4, 2012 11:06 AM writes...

It was never clear to me what this initiative was intended to provide or deliver. The most value in "screening" is the compound library which is available, as almost any facility can now conduct adequate assays (if they pay attention to the relavent Biology, and don't try to be too clever in insisting on using the most in-vogue "platform" to run a screen). How was NIH going to assemble better collections than available elsewhere? If there are no takers for the assets, then the whole thing should be simply shut down as soon as possilbe, saving NIH, government, and tax-payer funding.

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11. Zippy on March 5, 2012 6:58 PM writes...

As with most things in science, informed evaluation of the success of the ML program will require some time to allow the downstream effects to appear. The goal, as I understand it, is not to produce drug candidates, but to provide novel chemical probes for biological experiments. The primary reason for expensive failures in drug discovery is lack of efficacy in phase 2 studies. This mostly occurs due to a lack of understanding of the underlying biology. The ML aims to release to release hundreds of novel chemical probes for widespread use, which seems likely to increase the known pharmacology for some of these targets. This approach is similar to the practice of releasing tool compounds by some pharmaceutical companies, but on a large scale with wider input on target selection. Much of the intellectual input and mechanistic characterization comes from the academic community and the ML provides a vehicle for these people to more directly apply their efforts to human health and also to directly test their ideas in pharmacological experiments. This can only help the overall progress of drug discovery.

About the library. For the reasons described above, the compounds do not necessarily need to be drug-like. They simply need to be fit for cell or tissue-based experiments to be useful, in some cases. Most informed drug discovery programs would seek to do target validation studies in a simpler model before proceeding to in vivo studies where the demands, complexity and cost are much higher. Also, the library is small (300 K), but no less useful than larger libraries for finding novel hits.

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