Politburo Approved

Viral, tropical diseases are really cool because they have great names. e.g. Dengue or Breakbone Fever or Chikungunya ("that which breaks up").  The great thing about many viral diseases is that they are dependent upon proteases for many things. (And yes, I know how that sounds.)  Proteases have nice, well defined active sites that you can fill quite well and shut them down. In this paper, the authors use fragment-peptide merging to inhibit Dengue protease.  

This is really an extension of previous work.  The original work used capped peptides with a warhead with very good potency (down to 43 nM).  They then investigated retro, retro-inverse, semiretro-inverse, and nonretro di- and tri-peptides.  This lead them to use a tri-peptide (Arg-Lys-Nle) in two generations: first an arylcyanoacrylamide and then to N-substituted 5-arylidenethiazolidinone (thiazolidinediones and rhodanines).  These second generation hybrids had increased membrane permeability, in vitro binding, in cellulo antiviral activity.  Based on docking, they decided to investigate Nle sitting in P1', in contrast to previous site preferences and then merge it with fragments from an optimized capping moiety. 

1.  Starting Point Hybrid Peptide

The investigation of Nle replacements led to the phenylglycine molecule, with 4x greater affinity:

9.  Phenyl-glycine hybrid

They, then chose three hybrids (including 9) and put two different caps on them:

Rhodanine Cap

Acrylamide cap

Compared to the benzoyl cap, the acrylamide was 2x better while the rhodanine was 5x better.  But, wait, doesn't the Politburo condemn all uses of rhodanines?  Of course not.  In this case, the rhodanine was selected through rigorous analysis: and they have selectivity (this assay is fluorogenic).  They are perfectly aware of the general distaste people have for rhodanines and address the concerns. All of this together, leads to the final compound (below).

This is a really nice piece of starting with a tool (covalent peptides) and working to generate drug like molecules with favorable properties. 

PAINS Shaming, part deux

So, as regular readers know, we have declared war on PAINS on the blog.  As part of that effort, I (we?, not sure if Dan wants to be associated directly with it) introduced PAINS Shaming. Well, thanks to Angelo Pugliese and Duncan McArthur at the Beatson we have the latest paper to shame. 

The nice thing is that they come right out and call it like it is: a Rhodanine.  To reiterate, from the comment by Baell and Walters:

Rhodanines exemplify the extent of the problem. A literature search reveals 2,132 rhodanines reported as having biological activity in 410 papers, from some 290 organizations of which only 24 are commercial companies. The academic publications generally paint rhodanines as promising for therapeutic development. In a rare example of good practice, one of these publications (by the drug company Bristol-Myers Squibb) warns researchers that these types of compound undergo light-induced reactions that irreversibly modify proteins. It is hard to imagine how such a mechanism could be optimized to produce a drug or tool. Yet this paper is almost never cited by publications that assume that rhodanines are behaving in a drug-like manner.

And as predicted, this paper does not cite Voss et al.  They cite dose-depedent responses for their compounds.  Does it matter?  Not to me.  To their credit, they call these molecules tools, but also tout them for future therapeutic development.  A PAIN can be a useful tool or even lead to non-PAIN containing compounds, but it requires a higher level of proof.  I don't see that here. 

So, here is your PAINS Shaming (Holiday themed): 

Who's Reviewing this Crap?

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?