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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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April 4, 2013

Good Ways To Mess Up Your Screening

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Posted by Derek

For those of you interested in fragment screening (and especially for those who are thinking of trying it out), Ben Davis of Vernalis and Dan Erlanson of Carmot Therapeutics have written an excellent guide to avoiding the common experimental problems. (Remarkably, at least to me, Elsevier has made this an open-access article). In fact, I'd recommend the article to everyone doing early-stage compound discovery, whether they're into fragments or not, because many of the issues it raises are universal.

. . .Clearly the approach works, but that is not to say it is easy. This Digest focuses on an area we believe is still insufficiently appreciated: the myriad pitfalls and artifacts that can befall a fragment-screening program. For the sake of brevity, we have chosen to focus on the problems that can hinder or derail an experimental fragment screening campaign; a full discussion of issues around fragment library design, virtual fragment screening, and fragment evolution is best dealt with elsewhere. . .

. . .Today many techniques are used to identify fragments, each with its own strengths. Importantly, however, each of these techniques also has unique limitations. While expert users are generally aware of these and readily pick out the signal from the noise, newcomers are often deceived by spurious signals. This can lead to resources wasted following up on artifacts. In the worst cases—unfortunately all too common—researchers may never realize that they have been chasing false positives, and publish their results. At best, this is an embarrassment, with the researchers sometimes none the wiser. At worst it can cause other research groups to waste their own resources. . .

They go into detail on difficulties with compound identity and stability (on storage and under the assay conditions). You've got your aggregators, your photoactive compounds, your redox cyclers, your hydrolytically unstable ones, etc., all of which can lead to your useless assay results and your wasted time. Then there's a discussion of the limits of each of the popular biophysical screening techniques (and they all have some), emphasizing that if you're going to do fragment screening, that you'd better be prepared to do more than one of these in every campaign. (They are, of course, quite right about this - I've seen the same sorts of situations that they report, where different assays yield different hit sets, and it's up to you to sort out which of those are real).

Highly recommended, as I say. These guys really know what they're talking about, and the drug discovery literature would be greatly improved if everyone were as well-informed.

Comments (7) + TrackBacks (0) | Category: Drug Assays


1. petros on April 4, 2013 8:03 AM writes...

A very useful article and it is indeed free (for now)

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2. SP on April 4, 2013 8:09 AM writes...

Isn't this just Baell's PAINs work repackaged for fragments?

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3. John Wayne on April 4, 2013 8:34 AM writes...

I don't want to diminish the importance of the PAINs publications towards the education of screening pitfalls, but that all information was, itself, almost entirely already published in by industrial chemistry groups.

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4. Calvin on April 4, 2013 9:20 AM writes...

#3. That may be true but the PAINS paper brought it all together nicely. It's a very nice paper to be able to pull out when having a discussion with yet another group that wants to work on rhodanines. Which is still all to frequent....

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5. John Wayne on April 4, 2013 9:34 AM writes...

#4: I agree completely.

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6. Anonymous on April 4, 2013 11:37 AM writes...

Nice paper Dan.

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7. Anonymous on April 6, 2013 1:14 AM writes...

I think this is a paramount example of the effects that hype based science can have:
Some ten years ago, the HTS scene realized that it's not as easy as they told their management:
Just screen a mio compounds and there you go with your block buster. That's not gonna work and it's a big waste of time. More importantly, the early days of HTS were blind to knowledge that was already known. Look at early publications by Copeland etc. : Artifactual measurements were not first discussed by the HTS scene. It's just that they produced them in high throughput!
Now, when HTS got mature, the fragment guys entered the stage and of course needed to convince management. What's more appealing to management than smaller libraries, better quality, etc. But guess what! Screening at horribly high concentrations is just gonna increase the problems we've seen in HTS exponentially!
Perhaps we need to get rid of clusters like Cambridge where some hype based scientists just hook on the next company and next hype when they realized that the last hype failed. This in fact hinders progress... and leaves us with another 'Lessons Learned' article that states the obvious

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