So I reported here a couple of weeks ago that I’d obtained datasets for ACVR1 bound to M4K2117 and M4K2121, at 1.25 and 2 Å resolution, respectively, and I put up a link to the data. I’m now refining the data and got some pretty good structures so far. These are what the current stats look like, below. There’s still some way to go with the refinement, but they look pretty good so far!
I’ve also made some pretty pictures of the bound ligands, some or which were used for the M4K progress meeting yesterday. As can be seen below, the water molecule co-ordinating two of the Os on the trimethoxyphenyl is there, as in previous structures, and this is coordinated by another water and Lys235. The interaction of the hinge region of both ligands with His286 is also there. The solvent side is uncoordinated in the M4K2117 structure, but there’s a water there in M4K2121, which is less mobile in that region anyway, so that is not too surprising. It’s truly fabulous how we can easily see in these structures the chemical space that can still be explored to fill up the pocket, but I’m acutely aware of how many other important criteria a drug candidate has to fulfil in order to actually do its job properly. Hopefully, with the excellent expertise we have working on this project in all the different areas needed to make an effective drug, the structural information will be of use. Now, I have some more compounds to screen …
