tag:blogger.com,1999:blog-1136153439451224584.post1238053083508320046..comments2024-03-27T06:45:59.174-07:00Comments on Practical Fragments: Reagents as covalent fragmentsDr. Teddy Zhttp://www.blogger.com/profile/07288045760981372367noreply@blogger.comBlogger3125tag:blogger.com,1999:blog-1136153439451224584.post-71625968851065363862019-07-19T08:18:14.293-07:002019-07-19T08:18:14.293-07:00Thanks for the review Dan,
In fact, as you specul...Thanks for the review Dan,<br /><br />In fact, as you speculated, now several chemical suppliers offer boronic acid fragment libraries<br />Enamine - BAF-640-X-50 https://enamine.net/index.php?option=com_content&view=article&id=614&Itemid=1110<br />Key Organics - Key Organics have over 500 in-stock boronic acids available in small mg amounts for Fragment/HTS screening https://www.keyorganics.net/services/bionet-products/fragment-libraries/<br /><br />On the topic of inherent reactivity of boronic acids - water, by its abundance, typically out competes non-specific hydroxyls. Remember, these covenant interactions are reversible.<br /><br />A target with a complementary binding pocket, a serine or threonine with a hot hydroxyl and an oxyanion hole out-competes water<br /><br />Some bidentate hyroxyls such as pinenediol are tough for water to out-compete<br />Mark Hixonhttps://www.blogger.com/profile/01484062652236242871noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-43256400716873776792017-07-11T20:55:01.664-07:002017-07-11T20:55:01.664-07:00Hi Pete,
Actually, it's quite common to asses...Hi Pete,<br /><br />Actually, it's quite common to assess the inherent reactivity of warheads using a common nucleophile. In the case of thiol-reactive warheads this is usually glutathione or some other cysteine derivative. The Amgen <a href="http://pubs.acs.org/doi/10.1021/acs.jmedchem.5b01018" rel="nofollow">paper</a> I mentioned above does this for aryl acrylamides, and the researchers found a linear Hammett correlation. They also got good agreement between experimental results and density functional theory calculations.<br /><br />Another <a href="http://pubs.acs.org/doi/abs/10.1021/jm501412a" rel="nofollow">paper</a> from Pfizer looks at a more diverse set of irreversible warheads.<br /><br />The reason this is important is that if you have the same fragment with different warheads, and the warheads differ significantly in reactivity, you may think you are optimizing molecular complementarity when in fact you are just tweaking reactivity. Alexander Statsyuk has a nice discussion of this, covered <a href="http://practicalfragments.blogspot.com/2014/06/irreversible-fragments.html" rel="nofollow">here</a>.<br /><br />All of this also holds true for reversible covalent inhibitors, as discussed <a href="http://practicalfragments.blogspot.com/2013/05/reversibly-covalent-fragments-vs-kinases.html" rel="nofollow">here</a>.<br /><br />You are absolutely correct that "non-covalent interactions between target and ligand can potentially influence both on-rate and affinity", and these interactions can in fact be improved during lead optimization.Dan Erlansonhttps://www.blogger.com/profile/07927082337051189270noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-47567157548903435662017-07-11T02:20:26.555-07:002017-07-11T02:20:26.555-07:00Hi Dan, it’s not straightforward to calculate (or ...Hi Dan, it’s not straightforward to calculate (or even define) ‘inherent reactivity’ in a meaningful way for warheads that form covalent bonds with targets because non-covalent interactions between target and ligand can potentially influence both on-rate and affinity. I believe that it can be useful to label warheads as ‘reversible’ or ‘irreversible’ but it’s important to bear in mind that optimization of fragment hit affinity is likely to lead to a decrease in off-rate.Peter Kennyhttps://www.blogger.com/profile/12180360326821860667noreply@blogger.com