tag:blogger.com,1999:blog-1136153439451224584.post1689223125180828142..comments2024-03-27T06:45:59.174-07:00Comments on Practical Fragments: Upon RequestDr. Teddy Zhttp://www.blogger.com/profile/07288045760981372367noreply@blogger.comBlogger4125tag:blogger.com,1999:blog-1136153439451224584.post-67449328503945277892013-12-13T01:30:15.321-08:002013-12-13T01:30:15.321-08:00Dear All,
Thank you for your comments and feedbac...Dear All, <br />Thank you for your comments and feedback. You guys are expert in fragment-based-ligand design, so it is nice to see your feed-back on our work.<br />As we started with the fragment approach, we were young scientist never worked in this field before. We just realized that the tool compounds we were using to investigate the non-canonical G-quadruplex DNA were extended aromatic amines with low solubility in our cell studies. Therefore, we chose to go for a fragment approach to discover more soluble tool compounds. We found plenty of publications regarding classical targets such as proteins, however not much has been done to target DNA. <br />We actually have tested the top 10 fragments also in an secondary assay with an orthogonal read-out (SPR and NMR).<br />However, we have not show these data, because this will be part of a follow-up publication with a fragment growing phase.<br />Hamidhttps://www.blogger.com/profile/00151324460117039343noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-44593623850692322372013-12-13T01:12:27.385-08:002013-12-13T01:12:27.385-08:00Of course they know that anilines are mutagenic, e...Of course they know that anilines are mutagenic, especially when para substituted with EDG, but they included them in the library in an attempt to increase the hit-rateā¦.. good proof of principles but useless<br /> Anonymoushttps://www.blogger.com/profile/09009744735967943412noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-7650881108444275752013-12-12T20:27:50.376-08:002013-12-12T20:27:50.376-08:00I like the fact that they're using fragments t...I like the fact that they're using fragments to go after a tough target, but I have to agree with Teddy that more needs to be done to confirm that the fragments are behaving as proposed.<br /><br />Anonymous also brings up a good point about the anilines, which are problematic beyond their potential mutagenicity. The really worrisome observation is that all the anilines are para-substituted with an oxygen or nitrogen, making them prone to oxidation to yield reactive quinone-type species. Even if small amounts of these form, they could account for all the activity observed.Dan Erlansonhttps://www.blogger.com/profile/07927082337051189270noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-21500500238517795172013-12-12T18:34:36.174-08:002013-12-12T18:34:36.174-08:00AHHHHHHHHHHHHHHH!!!!!!!! Yet another fragment scre...AHHHHHHHHHHHHHHH!!!!!!!! Yet another fragment screen where the best hits are all compounds that you would not use in drugs. In this case these are all mutagenic anilines. The chemists will spend the next year and a half trying to find non-mutagenic replacements and spending mad $$$ on AMES screening. Eventually the program will be killed. But no one will say, "Hmmm. maybe pre should pre-filter our fragment deck." Oh wait, this is an academic group so they can just claim they are looking for "tool compounds"Anonymousnoreply@blogger.com