tag:blogger.com,1999:blog-1136153439451224584.post3159316509177854853..comments2024-03-27T06:45:59.174-07:00Comments on Practical Fragments: Seventh Annual Fragment-Based Drug Discovery MeetingDr. Teddy Zhttp://www.blogger.com/profile/07288045760981372367noreply@blogger.comBlogger6125tag:blogger.com,1999:blog-1136153439451224584.post-82804320235803914482012-04-29T04:01:18.922-07:002012-04-29T04:01:18.922-07:00As an xray crystallographer that saddens me a litt...As an xray crystallographer that saddens me a little bit. Some things are (next to) impossible to crystallize without a good ligand.<br /><br />How was the age distribution between the people who thought FBDD was possible without SBDD and those who didn't by the way?Morten Gnoreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-18280702577751215902012-04-26T01:31:35.061-07:002012-04-26T01:31:35.061-07:00Generally, having a lot of SAR means that you alre...Generally, having a lot of SAR means that you already have elaborated leads and are well set up for scaffold-hopping. That said, there is still scope for using fragments to establish further SAR efficiently (i.e. in terms of compounds synthesised). To do this, you will still need a reliable assay that is capable of measuring weak affinity. In FBDD, the power of the assay is defined (and limited) by the weakness of binding that can be measured.Peter Kennyhttps://www.blogger.com/profile/12180360326821860667noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-57908568271645887132012-04-25T18:49:31.179-07:002012-04-25T18:49:31.179-07:00Interesting comments Pete. Maybe we can start gett...Interesting comments Pete. Maybe we can start getting more people to share their opinion on the question.<br />I just would like to add something.<br />What if you do not have structural information but you have a lot of SAR available? Several patents, papers have been published on this particular target so if you have a fragment hit, you would have an idea of what to do with it based on the SAR available. I would think that in this case you can do FBDD without structure. As you nicely mention in your last commment, FBDD is less competitive with HTS in the absence of structure but this is true only if this is a new target with no SAR available.Anonymousnoreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-37070378344492962372012-04-25T01:48:12.191-07:002012-04-25T01:48:12.191-07:00The view that protein structural information is an...The view that protein structural information is an absolute requiremewnt for FBDD may reflect the types of target (e.g. soluble enzymes) that the approach has been mainly used against. The targets most suitable for fragment screening by biophysical methods (e.g. SPR, NMR) are often those which are most amenable to protein structural studies. <br /><br />That said, FBDD in the absence of protein structure will require a lot of synthesis. The chemists will need to start thinking about benzene rings as synthetic handles rather than as substituents. FBDD without protein structures will require a lot of careful, iterative (and honest) hypothesis-driven design. <br /><br />My own view is that FBDD is primarily just a smart (i.e measure rather than rely on a flakey scoring function) way to do structure-based design. In the absence of structural information, FBDD becomes less competitive with HTS (which is not an option for many organisations). The number of target classes for which nothing is known about the structure will continue to decrease even if a crystal structure is not available for the specific target of interest.Peter Kennyhttps://www.blogger.com/profile/12180360326821860667noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-41347583231385173882012-04-24T19:26:11.724-07:002012-04-24T19:26:11.724-07:00I found it very interesting that so few scientists...I found it very interesting that so few scientists think that FBDD is a valid approach in the absence of structure. I would agree that looking at the x-ray structure of an initial fragment can reduce considerably the number of compounds you would have to make to convert the low affinity fragment into a potent molecule. However, in the "old days" of drug discovery , no structures were available and still drugs were discovered. To my opinion, it would still be possible to use a fragment approach in the absence of structure. You would just have to build hypothesis on the binding mode of your fragment then make molecule to demonstrate that your binding mode is valid. I hope in the future,more adventurous scientists would try to optimize fragment hits without structure and demonstrate the validity of this approach.Anonymousnoreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-49331775124834527642012-04-24T10:58:44.001-07:002012-04-24T10:58:44.001-07:00I really wish people would stop talking about '...I really wish people would stop talking about '2D fragments' and remember that atoms have Van der Waals radii. I would guess that hexamethylbenzene would be flatter (think of minimum distance apart of two parallel plates in contact with molecules) than diphenylmethane. Fraction of sp3 carbons isn't going to be much use here.Peter Kennyhttps://www.blogger.com/profile/12180360326821860667noreply@blogger.com