01 September 2014

PAINS in C&EN

Just a quick heads-up that Celia Arnaud has a nice story on pan-assay interference compounds (PAINS) in the latest issue of Chemical and Engineering News. Celia attended the PAINS symposium at the ACS meeting last month and spoke with several of the speakers for the piece.

As far as I know this is the first time C&EN has devoted an entire article to PAINS. It’s a fast read so I won’t summarize it here, other than to say that she does pick up on the concept of PAINS-shaming, which Teddy has also advocated. Although Practical Fragments has done some of this, most PAINS are not fragments, so it wouldn’t really be appropriate to do much of it here (though please visit HTSpains).

I do hope Celia’s article is widely read by practicing scientists, journal editors, and reviewers. The need for more PAINS recognition is amply illustrated by this article published in the most recent issue of J. Med. Chem. which reviews reported inhibitors of AP-1, many of them dubious. Let's hope that the C&EN piece cuts down on future pollution.

6 comments:

Anders said...

Hi. 2 Qs for the PAIN experts:
1. Is there a "complete/near-complete" list of pains found in literature somewhere (blogs/papers). Or maybe you can point to a comprehensive one. It would be a useful tool to hold future hits and libraries up against.

2. Should one expect/fear pains in commercial libraries (eg Maybridge). I know aggregators are hard to predict, but can i count on that they have removed H2O2 generators, Michael acceptors, S-S creating compounds?

Great blog btw.

Jonathan said...

While not wanting to self-cite, see this url and these refs to get a good idea of recognizing likely PAINS:

https://www.collaborativedrug.com/buzz/2010/03/08/guest-blog-dr-jonathan-baell/

Baell JB. Observations on Screening-Based Research and Some Concerning Trends in the Literature. Future Med. Chem. 2 (2010) 1529–1546

Baell JB & Holloway GA. New substructure filters for removal of pan assay interference compounds [PAINS] from screening libraries and for their exclusion in bioassays. J. Med. Chem. 53 (2010) 2719-2740

Baell JB. Redox active nuisance screening compounds and their classification. Drug Discov. Today 16, 840-841 (2011)

Commercial libraries tend to have 5-12% PAINS. Usually not removed. But not a big deal if you are aware....always be wary of any hit...it has to prove itself right and not the other way around.

Anders said...

That is so great. Thanks Jonathan. I will study your interesting papers in more details...

Pete said...

Can you support the assertion that, "Commercial libraries tend to have 5-12% PAINS"?

Jonathan said...

HI Pete

See Table 7 of the PAINS paper.

That was from 2009 catalogs but a check minutes ago on a 2014 catalogue gives a similar value (9%) for the same vendor 5 years apart. So these will definitely turn up in hit sets from vendor-supplied compounds.

Mike said...

A few specific examples for Q.2.

% PAINS
GPHR (Minnesota) Library: 5.5% (primarily vendor libraries)
Three small (<50k), speciality libraries from Chembridge: 2.4, 4.3, 1.9 %

As of late last year eMolecules had ~6% PAINS.

Dahlin, J. L.; Walters, M. A. The essential roles of chemistry in high-throughput screening triage. Future Med. Chem. 2014, 6, 1265-1290.

Just out of curiosity...
%REOS (These values may not be as bad as they look since nitros, etc. are flagged by the REOS filters.)
GPHR (Minnesota) Library: 28.3%
Three libraries (same as above) from Chembridge: 6.3, 11.8, 6.2

Using filters as implemented in Canvas (Schrodinger).

The PAINS content will vary from collection to collection but, ss Jonathan points out, "trust, but verify."