tag:blogger.com,1999:blog-1136153439451224584.post7855116818609824919..comments2024-03-27T06:45:59.174-07:00Comments on Practical Fragments: STD-SPR smackdownDr. Teddy Zhttp://www.blogger.com/profile/07288045760981372367noreply@blogger.comBlogger6125tag:blogger.com,1999:blog-1136153439451224584.post-17885303009055739412013-01-28T06:44:07.927-08:002013-01-28T06:44:07.927-08:00I think it depends on what you mean by promiscuous...I think it depends on what you mean by promiscuous. Fragments that legitimately bind to multiple targets are probably fine - see:<br /><br />http://practicalfragments.blogspot.com/2011/08/fragment-selectivity.html<br /><br />and<br /><br />http://practicalfragments.blogspot.com/2011/10/privilege-or-selectivity.html<br /><br />What one does want to avoid are the pathological promiscuous binders, such as PAINS:<br /><br />http://practicalfragments.blogspot.com/2012/04/universal-fragments.htmlDan Erlansonhttps://www.blogger.com/profile/07927082337051189270noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-77855650468264602092013-01-27T09:20:36.204-08:002013-01-27T09:20:36.204-08:00Do this result call into question the logic of eli...Do this result call into question the logic of eliminating promiscuous binders since they turned up useful molecules in the NMR experiment? Finding a group that binds seems to be one of the major goals of FBDD since it is generally used on difficult to drug targets. Selectivity could be added during optimization.Anonymousnoreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-84483195949900339712013-01-22T21:17:38.608-08:002013-01-22T21:17:38.608-08:00Good comments all. Anonymous raises an interesting...Good comments all. Anonymous raises an interesting philosophical question about whether FBLD allows one to reach the global minimum as opposed to getting stuck in local minima. I guess the way I see it is that there isn’t necessarily a “perfect” drug for a given target, but rather a variety of possible drugs, assuming the target is druggable at all. One only needs to look at the number of effective statins, HIV protease inhibitors, VEGF inhibitors, and PDE5 inhibitors that are marketed, for example. <br /><br />FBLD can put you on a productive road, and if you end up in Paris rather than Rome, well, you’ll probably still have a good time!Dan Erlansonhttps://www.blogger.com/profile/07927082337051189270noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-21098752658695238282013-01-22T06:32:18.776-08:002013-01-22T06:32:18.776-08:00To state the obvious, it seems that early decision...To state the obvious, it seems that early decisions in FBLD can have a dramatic impact in later development. Being aware of those early decisions and biases is absolutely important.<br /><br />But does this example run counter to one of the major selling point of FBLD? It has been described that FBLD's major advantage (over traditional screening methods) is that you don't get stuck in local minima. I've heard the comparison to FBLD being a 10-foot ladder from which you can more accurately survey the drug discovery landscape, avoid those local minima and get to <i>the</i> global minimum.<br /><br />Do these results argue that FBLD is no different than screening? Or--in FBLD--do all roads lead to Rome?Anonymousnoreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-72929154028462989522013-01-22T04:28:01.064-08:002013-01-22T04:28:01.064-08:00I am fascinated by these results. So we saw last ...I am fascinated by these results. So we saw last year http://practicalfragments.blogspot.com/2012/04/seventh-annual-fragment-based-drug.html that the same fragment can be identified for different and be progressed into a lead. Now, we see that same fragments against the same target lead to different compounds based upon the detection method and how you define a hit.Dr. Teddy Zhttps://www.blogger.com/profile/07288045760981372367noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-35536011357684326102013-01-21T09:28:02.444-08:002013-01-21T09:28:02.444-08:00Another important reason for the initial lack of o...Another important reason for the initial lack of overlap in this study is that the SPR group eliminated fragments that were not selective for the target. Many compounds were eliminated in the SPR study b/c they bound to the desired target, and also to a secondary target. These results show that non-selective fragments in SPR could potentially be identified as hits in NMR studies. Another Venn diagram that accounts for this variance would show greater overlap between the NMR and SPR methods. <br /><br />The authors state the following........."Therefore, it appears that the selection criteria for classification of a hit in the different approaches, rather than the different conditions that were used, were a major reason for the lack of overlap."<br />Anonymoushttps://www.blogger.com/profile/15339876936614478464noreply@blogger.com