Flexible poses of macrocycles

Earlier today I set up 1056 crystallizations of the macrocycles my students Joanne and Serge gave me. We are keeping our fingers crossed that we will get something cool in these experiments…

As long as we are on the subject of macrocycles, I have to admit that they are really in the league of their own in terms of the insane conformational space they sample. There is no wonder researchers are having a tough time modelling them in the context of biological receptors. People only say macrocycles are rigid – they are certainly not! Here is a very cool case that shows how difficult it is to navigate through the conformational space of a macrocycle. Elena showed me this paper by Waugh and colleagues:

http://www.sciencedirect.com/science/article/pii/S0022283605009745

This work describes a macrocyclic SH2 domain inhibitor shown below:

Image

Here is a quote from the paper: “The sodium salt of S1s was dissolved in water and added to the highly pure Grb2 SH2 domain at 1.5:1 ligand to protein molar ratio. The complex was heated at 50 C for 10 min … before crystallization experiments were set up”. Are you kidding me? If you do not cook this thing up together with its target protein, it just won’t find the right pose. Big-time food for though here…

I am in San Francisco now (in Palo Alto to be exact). Tomorrow I am at Anacor and I will blog about my visit.

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