Dan and I teach a short course on FBDD; next chance to catch a version in October. My favorite part of Dan's section is when he goes off on PAINS and the continuing pollution of the literature. Rhodanines in particular get Dan's dander up. I often come off as anti-academic because many of their "drug discovery" papers are crap. Or they claim something is a lead without it being one. I think it is time to start PAINS shaming these papers. For those of you not intimately familiar with "shaming" it is very popular with dog shaming. Well, here is our first PAINS Shaming. This paper (pointed out by Matt Netherton at B-I, thanks Matt!) unabashedly points out the offensive molecule as a rhodanine. In the article, they point out:
What is particularly interesting about the most active species investigated here is that it has a structure that is very similar to that found in the drug epalrestat, an aldolase reductase inhibitor that is used to treat diabetic neuropathy, and is approved for clinical use in Japan, China, and India. This is encouraging because rhodanines as a class are known to often have activity in widely different assays, and indeed computer programs such as PAINS categorize, [our compounds] (as well as epalrestat) as possible “pan assayinterference compounds”. This can mean that the compounds cause false positives in assays, or that they may be multitarget inhibitors. In some cases multitargeting may be undesirable; however, in the context of anti-infective development, multitargeting is expected to increase efficacy as well as decrease the possibility of resistance development, both very desirable features.
I am sorry, but this is exactly the Underpants Gnomes business plan. All I can say after reading this is who's reviewing this crap and saying it is all right?
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7 comments:
Could it be that it is being reviewed by other academic groups who would also consider the PAINS badge of honor to be, err, an honor?
"What we have here . . . is a failure to communicate."
Oh! You are rude )
maybe this compound just disrupt the membrane of bacteria?
Well... half the molecule looks a lot like a known drug.... no reason to be concerned about off target effects/ cytotoxicity then :-)
I've reviewed several "drug DESIGN" papers by the McCammon group and each time recommended rejection. However, each time the paper made it in print. I guess that each time McCammon, an eminent MD simulations specialist, sweet talked the editor into accepting his paper.
McCammon, however, knows as much about what makes a drug candidate as the man who collects your garbage. As Socrates said more than two millenia ago "some people know a lot in one field, but then they make the mistake of thinking that they know a lot in all fields.
The quoted paragraph reads like a referee got annoyed with the structure of the active molecule and Epalrestat was dug up by the authors in the revised manuscript in an attempt to deflect the blow. Editors frequently make a judgment call without passing the manuscript back to the reviewer, especially if the other reports are ok.
Ironically, it almost sounds as though they've somehow taken a positive out of the PAINS paper itself which in part acknowledges that "Epalrestat, which is marketed in Japan as an aldose reductase inhibitor for treating
diabetic neuropathy (and more recently launched in India), contains a rhodanine-based
PAIN structure but does not appear to have poor pharmacokinetics". But when taken in context, in no way should this be seen as positive. Actually, I have not found out whether this drug is dispensed anywhere at all, and I am told it would never get close to market today
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