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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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February 8, 2010

Polluting the Literature with PAINs

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Posted by Derek

There's an article out from a group in Australia on the long-standing problem of "frequent hitter" compounds. Everyone who's had to work with high-throughput screening data has had to think about this issue, because it's clear that some compounds are nothing but trouble. They show up again and again as hits in all sorts of assays, and eventually someone gets frustrated enough to flag them or physically remove them from the screening deck (although that last option is often a lot harder than you'd think, and compound flags can proliferate to the point that they get ignored).

The larger problem is whether there are whole classes of compounds that should be avoided. It's not an easy one to deal with, because the question turns on how you're running your assays. Some things are going to interfere with fluorescent readouts, by absorbing or emitting light of their own, but that can depend on the wavelengths you're using. Others will mung up a particular coupled assay readout, but leave a different technology untouched.

And then there's the aggregation problem, which we've only really become aware of in the past few years. Some compounds just like to stick together into huge clumps, often taking the assay's protein target (or some other key component) with them. At first, everyone thought "Ah-hah! Now we can really scrub the screening plates of all the nasties!", but it turns out that aggregation itself is an assay-dependent phenomenon. Change the concentrations or added proteins, and whoomph: compounds that were horrible before suddenly behave reasonably, while a new set of well-behaved structures has suddenly gone over to the dark side.

This new paper is another attempt to find "Pan-Assay Interference" compounds or PAINs, as they name them. (This follows a weird-acronym tradition in screening that goes back at least to Vertex's program to get undesirable structures out of screening collections, REOS, for "Rapid Elimination of, uh, Swill"). It will definitely be of interest to people using the AlphaScreen technology, since it's the result of some 40 HTS campaigns using it, but the lessons are worth reading about in general.

What they found was that (as you'd figure) that while it's really hard to blackball compounds permanently with any degree of confidence, the effort needs to be made. Still, even using their best set of filters, 5% of marketed drugs get flagged as problematic screening hits - in fact, hardly any database gives you a warning rate below that, with the exception of a collection of CNS drugs, whose properties are naturally a bit more constrained. Interestingly, they also report the problematic-structure rate for the collections of nine commercial compound vendors, although (frustratingly) without giving their names. Several of them sit around that 5% figure, but a couple of them stand out with 11 or 12% of their compounds setting off alarms. This, the authors surmise, is linked to some of the facile combinatorial-type reactions used to prepare them, particularly ones that leave enones or exo-alkenes in the final structures.

So what kinds of compounds are the most worrisome? If you're going to winnow out anything, you should probably start with these: Rhodanines are bad, which doesn't surprise me. (Abbott and Bristol Myers-Squibb have also reported them as troublesome). Phenol Mannich compounds and phenolic hydrazones are poor bets. And all sort of keto-heterocycles with conjugated exo alkenes make the list. There are several other classes, but those are the worst of the bunch, and I have to say, I'd gladly cross any of them off a list of screening hits.

But not everyone does. As the authors show, there are nearly 800 literature references to rhodanine compounds showing biological effects. A conspicuous example is here, from the good folks at Harvard, which was shown to be rather nonspecifically ugly here. What does all this do for you? Not much:

"Rather than being privileged structures, we suggest that rhodanines are polluting the scientific literature. . .these results reflect the extent of wasted resources that these nuisance compounds are generally causing. We suggest that a significant proportion of screening-based publications and patents may contain assay interference hits and that extensive docking computations and graphics that are frequently produced may often be meaningless. In the case of rhodanines, the answer set represents some 60 patents and we have found patents to be conspicuously prevalent for other classes of PAINS. This collectively represents an enormous cost in protecting intellectual property, much of which may be of little value. . ."

Comments (11) + TrackBacks (0) | Category: Drug Assays | Drug Industry History | The Scientific Literature


COMMENTS

1. anchor on February 8, 2010 10:56 AM writes...

We encountered many of the problems discussed herein. Where I worked, the mangement wasted lot of time formulating thoughts as to what should happen next. The same sub-structure will show up for various program and we addtionally wasted even more time validating not only the structure but also the assay. But understand that from the time we hit it off, cross check, structural integrity and so on, an year rolls by with nothing to show. The people who head these program walk off with huge bonuses, while those who actually did the spade work were switched off to the next project.

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2. Anonymous on February 8, 2010 12:42 PM writes...

Actually, televancin (from Theravance) is a Mannich product of the bisphenol in vancomycin. So I wouldn't a priori eliminate that functionality.

What I have observed to be a ubiquitous hit from HTS were triamino triazines derived from cyanuric chloride. This was left over from the combichem heyday. They would show up in every screen regardless of what type of screen it was - enzyme, nuclear receptor, 7TM, ion channel ect. I would just shake my head anytime someone put one up as a bonafide hit from a screen.

From my standpoint, they were just way too close to herbicides like atrazine. So I'd throw them out when I was filtering the screen but I would never tell management. They loved them because any idiot could make them and you could make a lot of them very quickly - you know, metrics and stuff. Maybe there's a drug out there with a triamino triazine but I don't know it. There IS a food supplement from China but that doesn't count since it's quite toxic.

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3. Chris on February 8, 2010 12:45 PM writes...

I thought this was a very interesting paper and I await with interest for a succession of comments with similar tales of woe.
Frequent hitters are pretty near the top of my list of things to eliminate during analysis of HTS results.

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4. Questioner on February 8, 2010 3:38 PM writes...

Question:

Is it worth separating "poorly behaved in HTS assays" from "never could be a drug?" Let me ask this another way, would any of you old hands be more amenable to working on a putative frequent hitter if, rather than coming from an HTS, it came from a microarry experiment, or high-throughput fragment crystal soaks, or Biacore, or some other technique which has a different "specious result profile" than HTS. Because all this paper is really saying is that these compounds don't work well with our man-made reductionist systems for interrogating chemical space, not that they don't work well for binding to and perturbing biological targets.

Or do the two correlate?

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5. Mat Todd on February 8, 2010 3:56 PM writes...

Baell gave this talk at Sydney a short while back, and it was fascinating. Would be nice if rhodanines were good for something else, given how many are probably kicking around in the back rooms of pharma.

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6. DLIB on February 8, 2010 5:04 PM writes...

@ Questioner:

You are correct sir.

Extensive studies have been performed on this question. Every technology you mentioned creates systematic biases. Some are orthogonal to each other some are not.

Right answers Schmight answers it's only $1Bn bucks :-(

The industry will not invest in new technology / instruments and the vendors are happy selling the fluorescent compounds and engineering new ones.

It funny how at the mercy the pharmaceutical industry is to the instrument vendors ( who also own and engineer most of those great reagents -- keep throwing them down the drain....they'll happily make you more)

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7. Jonathan Baell on February 8, 2010 5:47 PM writes...

Just to qualify - the fact our filters recognize a small percentage of drugs is not really meant as an indictment for the drug, but rather to illustrate that we do not claim that our filters perfectly discriminate between drug and non-drug....because they weren't designed to; our main point here is that HTS hits recognised by our filters are far more likely to be unoptimizable than end up going all the way, so removing them in the first place is more beneficial than the vanishingly small chance that they will end up being a drug. We further note that the moieties that cause these marketed drugs to be recognized by our filters oddly also tend to be associated with met/PK/tox issues. We discuss this extensively in the Suppl Info (pp S59-60

On triazines: apart from the problematic IP space, we too find some triazines (for reasons currently unknown to us) and briefly mention this class (see p "J" in the JMC ASAP and SI p 77 in supp)

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8. Evorich on February 9, 2010 8:26 AM writes...

Surely the key is to maintain a dynamic, and relatively small (

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9. Evorich on February 9, 2010 8:53 AM writes...

Amino triazines surely pop up in several drugs; e.g. lamotragine.

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10. Anonymous on February 10, 2010 10:48 PM writes...

@ Evorich: lamotragine is a 1,2,4-triazine and I was referring to 2,4,6-triamino-1,3,5-triazines which are derived from cyanuric chloride. Hope that clarifies things.....I wouldn't lump lamictal in that class.

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11. Raphael Belcourt on August 12, 2012 9:48 AM writes...

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