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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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June 17, 2013

Aggravating Aggregators

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Posted by Derek

Compound aggregation is a well-known problem in biochemical assays (although if you go back a few years, that certainly wasn't the case). Some small molecules will start to bunch up under some assay conditions, and instead of your target protein getting inhibited by a single molecule of your test compound, the protein could look as if it's been inhibited by virtue of being dragged into a huge sticky clump of Test Compound Aggregate.

A group at Boehringer Ingleheim has a paper out in J. Med. Chem. suggesting a simple NMR readout to see if a given compound is showing aggregation behavior. It looks useful, but there's one thing I would add to it. The authors mention that they used a simple sodium phosphate buffer for their experiments, and that similar trends were observed in others (for a "limited set of compounds"). But I've heard Tony Giannetti of Genentech speak on this subject before (with reference to his specialty, surface plasmon resonance assays), and he's been pretty adamant about how situation-dependent aggregation can be.

The Shoichet lab's "Aggregator Advisor" page agrees. My worry is that some people might read this new paper and be tempted to clean their screening sets out up front, but you could throw some useful compounds out that way. But aggregation, annoyingly, appears to be a case-by-case thing. Probably the best ways to guard against it are (1) see if your assay can be run with detergent in it to start with, and be prepared to vary the amount, and (2) take your screening hits of interest and check them out individually before you decide that you're on to something. This new NMR assay would be a good way to do that, using the buffer that your screen was run in.

Another note that comes up in all discussions of aggregators is that while many of them are condition-specific, others have a wider range. Many "frequent hitter" compounds turn out to aggregate under a variety of conditions. In that case (because you've got empirical data from your own assays), it's really worth going back and flagging those things. It would seem worthwhile to go through any screening collection and pitch out the individual compounds that show up time and time again, since these are surely less likely to lead to anything useful. Some of these will, on closer inspection, turn out to be promiscuous aggregators, but there are other mechanisms for nastiness as well. In extreme cases, whole structural motifs should be given the fishy eye.

Comments (6) + TrackBacks (0) | Category: Drug Assays


1. dearieme on June 17, 2013 8:55 AM writes...

O/T: new rules to try to stop the faking of results.

I suppose that spells trouble for the University of East Anglia and the Met Office?

Permalink to Comment

2. ScientistSailor on June 17, 2013 12:39 PM writes...

It's great to see warnings non-specific activity continue to appear. We have wasted a tremendous amount of time chasing down junk, and it is time to put a stop it. I've recently been sent two papers for review wherein the lead matter were PAINS, and there was no diligence was done to eliminate aggregation. I summarily rejected these papers, and sent along a copy of the Baell paper as a parting gift.

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4. A. Student on June 18, 2013 1:00 PM writes...

@ScientistSailor I'd be interested to know if your rejections were respected by the editor. I rejected papers for similar reasons and the editor just ignored it. Of course, since the PI on the paper and the editor have a company together, which neither declares in any of their conflict of interest statements, I can only assume the reviewing is just a formality.

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5. Sili on June 18, 2013 3:04 PM writes...

I suppose that spells trouble for the University of East Anglia and the Met Office?
The Met Office does drug research? Permalink to Comment

6. ScientistSailor on June 18, 2013 3:46 PM writes...

Student, I think one of the papers was rejected, at least I never saw it in the Journal it was submitted to. It was also a terrible paper for other reasons.

The second example is in process, I don't know the result yet.

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