Rongjin, (As you may know) there is considerable precedent for soaking mixtures of small fragments into crystals. If you choose compounds to be shaped differently, you can determine which compound is bound by the shape of the electron density map for the ligand. I would not be concerned about similar binding affinities - in practice it is very difficult to achieve binding of two competing fragments. Affinities, solubilities, concentrations would all have to be just right. I've never seen it in over 10 years although someone out there might have and I would be personally interested. Feel free to contact me directly if you would like references etc. They are on our web-site which unfortunately is down and being updated today. Good luck, Vicki Nienaber Zenobia Therapeutics
From: CCP4 bulletin board [mailto:ccp...@jiscmail.ac.uk] On Behalf Of Rongjin Guan Sent: Thursday, November 12, 2009 1:57 PM To: CCP4BB@JISCMAIL.AC.UK Subject: [ccp4bb] small molecule soaking screening Hi All Sorry that this is a non-ccp4 question, but I hope I can get some good suggestions from the community. We have protein crystals under various conditons and want to soak them with different potential inhibitors. Most of inhibitors have very small molecular weights (200-300), so it become a problem how to detect if the small compounds have been soaked into the crystals or not. (co-crystallization experiments yielded no hits so far, though the free form is easy to be crysatllized under many conditions) We pay $500/day for local X-ray facility access, so we wonder if there are some more efficient ways that allow us to know if the small compounds soaked in or not, without collecting a whole data set for MR. We are also thinking if we can mix several compounds together for soaking, to reduce the combinations of soaking experiments with various compounds and crystals from various conditions. Is this practical, if some of them have pretty similar binding affinities to the protein? All comments/suggestions are welcome. Thank you Rongjin Guan
