Viewing C-H bonds while getting annoyed

I was putting together some finishing touches on a set of notes for tomorrow’s class on heterocyclic chemistry. Over the past year I have developed a strong appreciation of aromatic heterocycles, which is mainly due to my lab’s current interest in how to put these systems together using boron transfer reagents. While I was doodling some thiazoles on a sheet of paper, I was thinking about the utility of these molecules as kinase inhibitors. Many heterocycles endowed with hydrogen bond donor/acceptor motifs are capable of establishing contacts at the kinase hinge region. Specificity is another question, but let’s set it aside for now. When you look at the thiazole core, it is tempting to ask a seemingly ludicrous question: “What about that CH bond next to the acceptor nitrogen? Can it interact with the protein backbone?” I brushed this thought away as heresy, but it kept coming back. So I said: “OK, let’s look at the literature. There is no way there is anything remotely close to this silliness out there”. Well, it turns out I was wrong – there is a very interesting report from Vertex, wherein the CH bond in question has been implicated in a hydrogen bond with the hinge region. This gives me a chance to vent about one of my pet peeves: do not publish papers in ACS journals unless you are willing to deposit the coordinates of your structures in the pdb! The example below can be a very useful and instructive tool in medicinal chemistry classes. As they say, a picture is worth a thousand words. However, if you are not willing to let us download the pdb file (due to patent considerations, of course), do not publish it in a chemistry society journal. Submit it to the Proceedings of the Transylvanian Society of Patented Inventions instead. I hope people at Vertex and other companies hear me. Instead of my usual picture with a visually appealing view, I am forced to offer a ChemDraw rendition of the interaction.

CH bond

http://pubs.acs.org/doi/abs/10.1021/jm0492249

4 thoughts on “Viewing C-H bonds while getting annoyed

  1. Another notable feature here is the “N-S bond” – Because thiazoles and thiophenes have partial positive charge on sulfur, they like to orient themselves in plane with a nearby ring (or amide bond) so that an electron pair donor (heterocycle nitrogen, amide carbonyl) is pointed towards sulfur. It is a useful trick for making rigid fixed conformation ligands without actually constraining them by addition of a covalent or hydrogen bond.
    This effect is a common knowledge in kinase field but it is rarely mentioned in medchem textbooks.

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