tag:blogger.com,1999:blog-1136153439451224584.post3247033855012070859..comments2024-03-27T06:45:59.174-07:00Comments on Practical Fragments: Poll Results: Do you Need StructureDr. Teddy Zhttp://www.blogger.com/profile/07288045760981372367noreply@blogger.comBlogger4125tag:blogger.com,1999:blog-1136153439451224584.post-31303257143247841742012-09-08T20:00:05.860-07:002012-09-08T20:00:05.860-07:00I apply NMR protein labeled for frag. hits (parall...I apply NMR protein labeled for frag. hits (parallel with x-ray) and it works perfectly for me. A bit expensive but certainly worth it. Crystallography with frag. is rather difficult, also they bind quite often without any sense which might be misleading.Anna Tochowicznoreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-67051131296279065402012-08-31T10:52:32.323-07:002012-08-31T10:52:32.323-07:00I go with STD NMR. In particular with fragments I ...I go with STD NMR. In particular with fragments I found the risk of running into the spin-diffusion induced epitope rather limited.Anonymousnoreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-89530707932734189342012-08-30T08:07:29.847-07:002012-08-30T08:07:29.847-07:00Hope there will be some interesting comments on th...Hope there will be some interesting comments on this poll. With limited experience and then only from having a second-site binders, I would prefer having ilNOEs between the ligands. <br /><br />Or, as in one case of mine where there is a peptide-bound structure but no fragment-bound structures. Then I would consider NOEs for each fragment to the protein, that can be used for restraint-driven docking, very helpful. This might limit the chemistry effort required. But at some point you probably want to do some SAR by more "brute force" as well, to find out if you really got it right.Anonymousnoreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-80936603116913199362012-08-30T06:57:14.880-07:002012-08-30T06:57:14.880-07:00I agree that structures are helpful, but not essen...I agree that structures are helpful, but not essential. One of my favorite examples of advancing a fragment in the absence of structure was for FtsZ (see <a href="http://practicalfragments.blogspot.com/2009/01/ligand-efficiency-for-antibiotics.html" rel="nofollow">here</a>). They actually did methyl, ethyl, propyl, butyl, all they way to nonyl, entirely bypassing futile!<br /><br />It's easy to forget in these structurally rich times that people were inventing drugs long before any proteins were characterized by crystallography, let alone NMR. Following good old-fashioned SAR works well for membrane proteins, and to some extent it just takes an open mind to apply some of these same strategies to fragments.Dan Erlansonhttps://www.blogger.com/profile/07927082337051189270noreply@blogger.com