tag:blogger.com,1999:blog-1136153439451224584.post1863603249130864126..comments2024-03-27T06:45:59.174-07:00Comments on Practical Fragments: How weak is too weak for PPIs?Dr. Teddy Zhttp://www.blogger.com/profile/07288045760981372367noreply@blogger.comBlogger5125tag:blogger.com,1999:blog-1136153439451224584.post-2987706168750319642014-02-07T01:45:00.889-08:002014-02-07T01:45:00.889-08:00I interpreted the original question slightly diffe...I interpreted the original question slightly differently in that I thought it was asking at what point do you give up because although your fragment derived molecule is pretty potent, you’re still not seeing any inhibition in a functional assay?<br /><br />The answer to that is going to vary depending on the MoA of the cpd, but if you’re working with fragments that compete with substrate, you’d only predict a 2 fold loss in potency on going into an enzyme assay if you run it at Km.<br />Anonymousnoreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-21343581279705888272014-02-06T00:45:21.283-08:002014-02-06T00:45:21.283-08:00A brief comment to Christophe: Compound 6 includes...A brief comment to Christophe: Compound 6 includes many of the atoms from the other two compounds, hence, I think it is not fair to do a straight analysis of the three Kds. The affinity of compound 6 has to be scaled down.Andersnoreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-83795785774034411802014-02-05T02:38:35.720-08:002014-02-05T02:38:35.720-08:00Clearly these are weakly-binding fragments but the...Clearly these are weakly-binding fragments but there are examples of progressing 10mM fragments to nM, biochemically-functional PPI inhibitors. <br /><br />If optimisation proves to be difficult or impossible, organisations need to find ways to stop projects in a timely way. Target validation will always be an issue and FBDD does not solve that. <br /><br />On the question of LLE as a marker for X-ray detection of the hit, I would suspect that solubility is actually the underlying parameter....Glyn Williamsnoreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-10700758068187720212014-02-03T14:04:25.051-08:002014-02-03T14:04:25.051-08:00I doubt that the fragments bind similarly on their...I doubt that the fragments bind similarly on their own as they do in the parent molecule because of the following thermodynamic argument. If we translate the Kds into kcal/mol, sum them and translate the sum again into a Kd we arrive at 0.062 microM or 25 times better than the observed 1.5 microM. If the linking were perfect the Kd for the mother compound should even be at least 1000 times better, thus sub nM, because of paying a lower entropic cost when the fragments are bound.Christophehttps://www.blogger.com/profile/16644725678417246202noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-61525929510430628972014-02-03T07:10:00.897-08:002014-02-03T07:10:00.897-08:00I think it's a bit more insidious than simply ...I think it's a bit more insidious than simply asking "how potent does binding need to be to see functional activity". The question truly is "will any molecule that binds to this binding site have functional consequences"? The answer is often "no", leading to months-long optimization campaigns that lead to great binders with do nothing (that can be detected) useful. All the while, the chemists and biologists "discuss" the reasons . . . Anonymousnoreply@blogger.com