Whichever way the wind blows

I was out of town over the past two weeks, which explains the absence of blog posts. I am now trying to get back into my usual rhythm. Tonight I want to talk about some fine lines in chemistry or, more accurately, some “blurred boundaries”. An interesting essay came out in Nature not too long ago. My co-worker Conor Scully brought it to my attention: http://www.nature.com/news/chemistry-chemical-con-artists-foil-drug-discovery-1.15991. In this paper, the authors lamented about scaffold promiscuity in drug discovery. Promiscuity arises when a molecule interacts with many targets, which may lead to manageable polypharmacology in the best case and total mess in the worst. There are many reasons for particularly terrible outcomes and they range from compound aggregation to metal ion sequestration and covalent protein modification. Covalent inhibitors are the most common culprits, but there are many non-covalent “offenders”, such as 2-aminothiazole. In fact, it was Diego Diaz, my PhD student, who started today’s discussion at our journal club by pointing out the dark side of 2-aminothiazole: http://pubs.acs.org/doi/full/10.1021/jm501402x. Here is my problem with all of this: as I peruse these papers, I cannot help but recall the concept of a privileged scaffold. Snyder and co-workers did a nice job describing this notion some time ago: http://www.sciencedirect.com/science/article/pii/S1367593110000232. By definition, a privileged scaffold is expected to interact with many targets, which allows synthetic chemists to write long-winded intros in their methodology papers. These opuses speak to the projected veracity of developing a new method of making some trisubstituted pyridine (or whatever else). But hold on, my friends. I sense a bit of a conflict: a molecule that interacts with too many targets can be “trashed” for its promiscuity, yet the same molecule can appear in the “privileged scaffold” cohort. This is some double standard.

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