tag:blogger.com,1999:blog-2909827059962062852.post2125663784676818949..comments2024-03-26T17:10:36.305+00:00Comments on Molecular Design: There's more to molecular design than making predictions Peter Kennyhttp://www.blogger.com/profile/12180360326821860667noreply@blogger.comBlogger4125tag:blogger.com,1999:blog-2909827059962062852.post-38756911118519323922015-02-22T17:10:15.763+00:002015-02-22T17:10:15.763+00:00I guessed as much so no worries. In my orginal com...I guessed as much so no worries. In my orginal comment on the In the Pipeline post I'd said the opposite of what I meant to say with respect to charge type symmetry so I know it's an easy typo to make.Peter Kennyhttps://www.blogger.com/profile/12180360326821860667noreply@blogger.comtag:blogger.com,1999:blog-2909827059962062852.post-64558367999705905432015-02-22T16:49:32.709+00:002015-02-22T16:49:32.709+00:00Sorry, meant to say increase logP.
Your reply is ...Sorry, meant to say increase logP.<br /><br />Your reply is exactly what I was trying to get across. If the compound is made to answer a particular targeted question of interest, then it's likely worth making. My beef is with making inactive compounds to somehow better understand the primary activity, by deliberately trying to break it.<br /><br />Lee H.Lee Hermanhttps://www.blogger.com/profile/11283011149659771491noreply@blogger.comtag:blogger.com,1999:blog-2909827059962062852.post-5239608424546979172015-02-22T16:28:07.057+00:002015-02-22T16:28:07.057+00:00Thanks for your comment. I think that we’re prett...Thanks for your comment. I think that we’re pretty much in agreement here although I would note that removal of a hydroxyl is likely to result in an increase in logP but let’s not worry about that. One hydroxyl group scenario is that we have a crystal structure of a protein-ligand complex and are looking to introduce a solubilizing group. Our hypothesis is that introducing a hydroxyl group at a particular position will be reasonably well tolerated by the complex (i.e. minimal loss of affinity) and we synthesize the compound(s) to quantify the effect on affinity. Nevertheless we'll be anticipating some loss of affinity. If we’ve got access to in house solubility data then we can do matched molecular pair analysis to get an idea of how much we expect the hydroxyl group to enhance solubility and it could well be that the informatics folk have already assembled this information so that it is ready to be used by project team members. Peter Kennyhttps://www.blogger.com/profile/12180360326821860667noreply@blogger.comtag:blogger.com,1999:blog-2909827059962062852.post-83018167098742889652015-02-21T18:56:51.554+00:002015-02-21T18:56:51.554+00:00Peter
I attended the talk, but did not get to com...Peter<br /><br />I attended the talk, but did not get to comment on the deliberate synthesis of inactive compounds.<br /><br />Briefly, I do not support the synthesis of compounds that are predicted to be inactive. There are a zillion (a real technical term) ways why a compound is inactive, but only a few why they are active. You just don't have time to figure out, or sample, all the reasons a compound would be inactive - you barely have time to figure out why they are active.<br /><br />On the other, it is worth a risk to make a compound that could be inactive, because you remove a functional group that you think could be essential, if the payoff is desirable (e.g. remove a hydroxyl to lower logP). But this is a different case from making the same compound just to see if you really need that same hydroxyl.Lee Hermanhttps://www.blogger.com/profile/11283011149659771491noreply@blogger.com