Pan-assay interference compounds – PAINS – are a topic that
has come up repeatedly at Practical
Fragments (see here, here, and here for starters). Indeed, they form the basis
of our occasional (and controversial) “PAINS shaming” series (see here, here,
here, and here). In a paper recently published online in J. Med. Chem., HTSPains-master Mike Walters (University of
Minnesota) and collaborators at the Mayo Clinic College of Medicine and AstraZeneca
characterize several new classes of PAINS (also covered at In the Pipeline). I was honored with the invitation to
write a Viewpoint on the topic. Since both papers are open-access I’ll just
briefly touch on a few key points here.
First, one of the only critics of the PAINS concept is
concerned that PAINS were originally defined on the basis of their over-representation
as screening hits in one set of assays. The new paper goes beyond empiricism to
characterize mechanisms, which involve non-specific reactions with thiols. (The
“non-specific” aspect is key to their undesirability, as covalent drugs can be
quite attractive.)
Second, just as “not every clam will hurt you”, not every
molecule with a PAINS substructure will show activity in every assay. These
“structure-interference relationships” (SIR) can be mistaken for
“structure-activity relationships” (SAR), making PAINS all the more insidious.
The researchers explore some of the reasons for the observed SIR.
Third, one of the saddest parts of the new paper is a list
of dozens of references in the supplemental information in which PAINS were
reported as screening hits or probes. It’s a safe bet that most – if not all –
of these should be disregarded.
Finally, publishing this list of new PAINS will allow people
to steer clear of them. To borrow from Hippocrates: chemical space is big, life
is short. Why waste time working with chemotypes known to be pathological?
Hi Dan, Just wanted to clarify a couple of points. I don’t think that it’s accurate to describe me as a critic of the PAINS concept (whatever that is). Criticisms I have made are primarily about whether evidence supports assertions made. I certainly agree that some (many?) of the hits from HTS are what I’ll call, in the interests of brevity, ‘pathological’ and many in Pharma have known this since the mid-90s (long before people talked about PAINS). Sets of rules for dealing with the junk were assembled in a number of Pharma companies and, while some of these were published, many were not. I believe rapid elimination of swill (REOS) was first described in the literature by Vertex in the late 90s so it is fair to say that the PAINS concept has been with us for quite a while. Just in case you’re interpreting my blog post on PAINS as evidence for Luddite tendencies and blind faith in the quality of HTS output, I’ll mention that I did write the SMARTS-based substructural analysis software that we used to apply the Zeneca ‘decrapper’ in 1995 specifically for dealing with HTS output.
ReplyDeleteWe observed frequent hitters right from the start but there were also compounds that looked plain nasty event thought they weren’t frequent hitters. The other thing we used to do in Zeneca was maintain an HTS matrix and this could be used to quantify correlations between assays (if anyone from AZ is reading this, there’s a program that I think is called HTS_CORR on a linux system somewhere that calculates the correlations). When we observed a high degree of correlation between assays, we looked for explanations. Did the assays use the same detection technology? Were the catalytic mechanisms of the enzymes related? The uglies that we identified on the basis of hitting both a cysteine protease and a PTP weren’t frequent hitters but thinking about the chemical structures and the common catalytic cysteine certainly set a few alarm bells ringing. Some of redox cyclers were picked up this way and their nastiness was characterized by some excellent (I believe unpublished) work by colleagues at Wilmington where I had been seconded to in the late 90s.
So back to PAINS. As noted in my blog post, the original PAINS article uses a panel of just 6 assays with the same detection technology. I don’t believe that you can simply invoke the original PAINS article to declare somebody’s work to be invalid and to do so would be a bit like beating somebody with a toothpick. The recent PAINS article that you reviewed is a very different beast in that chemical structures are disclosed and the essence of the PAIN is revealed in exquisite detail.
http://pubs.rsc.org/en/Content/ArticleLanding/2015/CC/C5CC00677E#!divAbstract
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