[ccp4bb]: Inhibitors do not show up in electron density maps after soaking

[Zsolt Bocskei <Zsolt.Bocskei@sanofi-synthelabo.com>]

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Dear All,

Recently I have found no inhibitors bound in an alarmingly large portion of the co-crystal structures that I examined. I would be grateful if people could send me their comments, experiences etc. on this topic. 
This seems to occur with relatively weekly binding, water insoluble inhibitors (let's say in the micromolar range). I dissolve them in DMSO or DMF in quite a high concentration (10-100 mmolar) and then I replace 1-10 % of my crystallization mother liquor ( or a more concentrated version of that) with this DMSO/DMF solution of the inhibitor and then I soak my "empty"/non-complexed crystals in this liquid. I have to admit that after mixing the inhibitor solutions with the crystallization mother liquor a lot (or most, or maybe even worse: perhaps all) of the inihibitor precipitates, but one can read papers in the literature when adding the powder form of the inhibitor to the crystallization droplet has also produced the required complexes and indeed I have had cases like that, too.
So again, in what portion of their experiments do other people get useless "results" like the ones described above and how do they treat these cases. If this is so frequent then I find can one consider the results of the high throughput crystallographically driven screening approaches reliable at all (many false negatives)? 
Sorry for being off topic and thanks for any help in advance.

Zsolt

Zsolt Bocskei
Sanofi-Synthelabo Recherche
16 rue d'Ankara
67000 Strasbourg
France
Tel:33(0)388454116
Fax:33(0)388459070