tag:blogger.com,1999:blog-1136153439451224584.post416307982127281887..comments2024-03-27T06:45:59.174-07:00Comments on Practical Fragments: From substrates to fragments – or notDr. Teddy Zhttp://www.blogger.com/profile/07288045760981372367noreply@blogger.comBlogger3125tag:blogger.com,1999:blog-1136153439451224584.post-88901296312197720162014-05-31T15:42:49.097-07:002014-05-31T15:42:49.097-07:00Unlike synthetic fragments in a biophysical assay,...Unlike synthetic fragments in a biophysical assay, most enzymes tend to be rather selective when it comes to their substrates. Co-evolution in a sea of metabolites has pressured enzymes to be selective; this helps prevent processing the wrong material. At Beryllium (formerly Emerald) we have seen "fragment" selectivity by NMR and crystallography, if the fragment in question is a nucleotide and is (or contained within) the native substrate or not. This mirrors the "small changes in the substrate hav[ing] pronounced effects" by enzyme assay in Sarah's paper. So perhaps the relatively lower selectivity and broader array of protein targets observed for more synthetic aromatic fragments (frequently reported in the literature and in this blog) has to do with such compounds more broadly (not so specifically) mimicking native substrates? Hence the non-fragment, computational approach with all known (exact, specific) metabolites (Suwen Zhao 2013 Nature paper) may have a better chance at divining exact substrates, if the relative docking scores can get there. <br /><br />Knowing this does not make going about narrowing down the exact function of a protein using fragments any easier, particularly for enzymatic functions as of yet undocumented (think bacterial genomes for organisms which can degrade almost anything). But I think there is still the possibility of a middle ground for fragments to play when the general function is unknown, if the right compounds happen to be in the collection. Maybe not each and every time, but if you're lucky.Darren W Begleyhttp://www.be4.comnoreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-39585528898689685142014-05-30T08:13:51.859-07:002014-05-30T08:13:51.859-07:00Kevin, the structure of Fragment 9 is taken direct...Kevin, the structure of Fragment 9 is taken directly from the paper and is, as drawn, a static THF analog and thus unable to equilibrate.Dan Erlansonhttps://www.blogger.com/profile/07927082337051189270noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-12844906991933530672014-05-30T08:00:40.468-07:002014-05-30T08:00:40.468-07:00There seems to be a misunderstanding of the chemic...There seems to be a misunderstanding of the chemical structure of fragment 9. As a sugar, there is the interconversion between cyclic and linear structures. In compound 1, the cyclic form is lock into place through the glycosidic linkage. The removal of this bond allows free interconversion and, as a result, a huge drop in activity. The drawing of fragment 9 as a static single structure is misleading as are conclusions about fragment linking. The use of a carbocylic (THF) analog of structure may provide a more appropriate comparison. Anonymoushttps://www.blogger.com/profile/00975165421300330544noreply@blogger.com