Talk:Proteolysis targeting chimera: Difference between revisions

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Wiki Education Foundation-supported course assignment

This article was the subject of a Wiki Education Foundation-supported course assignment, between 7 January 2020 and 14 April 2020. Further details are available on the course page. Student editor(s): Rhartsou.

Above undated message substituted from Template:Dashboard.wikiedu.org assignment by PrimeBOT (talk) 02:48, 18 January 2022 (UTC)[reply]

Wiki Education Foundation-supported course assignment

This article was the subject of a Wiki Education Foundation-supported course assignment, between 8 September 2021 and 19 December 2021. Further details are available on the course page. Student editor(s): Sarah5085.

Above undated message substituted from Template:Dashboard.wikiedu.org assignment by PrimeBOT (talk) 02:48, 18 January 2022 (UTC)[reply]

Chimera -> Chimaera

I believe that Chimaera is the correct spelling. This might require a minor page move, too. RogueTeddy (talk) 09:33, 24 March 2019 (UTC)[reply]

I added a citation to the Mechanism section --Rhartsou (talk) 20:26, 10 April 2020 (UTC)[reply]

College writing course

Hi, I am editing this page as part of a college writing course. I plan on updating the introduction, mechanism of action, and possibly including a development section. I'll link some of the new references I'll include later. Sarah5085 (talk) 15:22, 16 November 2021 (UTC).[reply]

@Sarah5085: Happy editing, and feel free to ask me if you need any help! --ἀνυπόδητος (talk) 07:37, 17 November 2021 (UTC)[reply]

Benefits

One claim is: " This also helps prevent mutation-driven drug resistance often found with enzymatic inhibitors." That does not follow at all. Any selection pressure to keep a protein functional applies equally to it being inhibited directly or indirectly targeted for degradation. In either case some sort of binding is required and so in either case there is just as much selection pressure to mutate the binding site away from the binding regardless of how the binding causes issues as the same binding mutations "cost the same" amount of biological fitness and have the same reward in persevering enzyme function. I.e. the difference in evolutionary selection pressure and risk + rate + reward of mutation is irrelevant if a small molecule binder causes inhibition directly, targets it for degradation, is a transponder that calls in a nano-scale smart missile, or magically summons little demons who simply keep the substrates from reaching the enzymes active site like little goalies intercepting shots. Any mechanism of enzyme function reduction real or purely imaginary is irrelevant in its difference on mutation selection pressure so long as the basis for initiating of the mechanism is binding. In all such cases the same selection pressures and mutational possibilities are equally in play and have the same risk and rewards. Worse, the statement as situated implies that because degraders can bind outside of the active site this reduces mutational issues, which is doubly wrong -- the non-active site surfaces of a protein are often orders of magnitude more permissive in mutational tolerance then the active site, as the active site is the most precisely tuned and delicate portion of the entire protein. This has been found with allosterically regulating enzyme inhibitors -- they bind outside of the active site and cause a change in protein conformation to shut it down. Such allosteric enzyme inhibitors can be extremely useful especially as they are typically non-competitive binders v.s. substrate, but in cases where there is strong mutation selection pressure, on average they are far more easily and quickly defeated by lower fitness-cost mutations then typical active site binding inhibitors.

Thus, in leu of a really good citation proving this at-face, on-paper, doubly-wrong statement currently made I think this statement should be removed. Additionally a "really good citation" would be one that actually has data to back up such an assertion instead of such an assertion just dumped into a paper unproven by a protac author who is "selling their wares" with lofty (but unproven) statements as many of us scientific authors are want to do from time to time very much to the discredit of what has become of modern science.162.220.42.222 (talk) 18:59, 26 May 2022 (UTC)[reply]

@@ Line 20: / Line 20: @@
 Hi, I am editing this page as part of a college writing course. I plan on updating the introduction, mechanism of action, and possibly including a development section. I'll link some of the new references I'll include later. [[User:Sarah5085|Sarah5085]] ([[User talk:Sarah5085|talk]]) 15:22, 16 November 2021 (UTC).
 :{{ping|talk:Sarah5085}} Happy editing, and feel free to [https://en.wikipedia.org/w/index.php?title=User_talk:Anypodetos&action=edit&section=new ask me] if you need any help! --[[User:Anypodetos|ἀνυπόδητος]] ([[User talk:Anypodetos|talk]]) 07:37, 17 November 2021 (UTC)
+== Benefits ==
+One claim is: " This also helps prevent mutation-driven drug resistance often found with enzymatic inhibitors."  That does not follow at all.  Any selection pressure to keep a protein functional applies equally to it being inhibited directly or indirectly targeted for degradation.  In either case some sort of binding is required and so in either case there is just as much selection pressure to mutate the binding site away from the binding regardless of how the binding causes issues as the same binding mutations "cost the same" amount of biological fitness and have the same reward in persevering enzyme function.  I.e. the difference in evolutionary selection pressure and risk + rate + reward of mutation is irrelevant if a small molecule binder causes inhibition directly, targets it for degradation, is a transponder that calls in a nano-scale smart missile, or magically summons little demons who simply keep the substrates from reaching the enzymes active site like little goalies intercepting shots.  Any mechanism of enzyme function reduction real or purely imaginary is irrelevant in its difference on mutation selection pressure so long as the basis for initiating of the mechanism is binding.  In all such cases the same selection pressures and mutational possibilities are equally in play and have the same risk and rewards.  Worse, the statement as situated implies that because degraders can bind outside of the active site this reduces mutational issues, which is doubly wrong -- the non-active site surfaces of a protein are often orders of magnitude more permissive in mutational tolerance then the active site, as the active site is the most precisely tuned and delicate portion of the entire protein.  This has been found with allosterically regulating enzyme inhibitors -- they bind outside of the active site and cause a change in protein conformation to shut it down.  Such allosteric enzyme inhibitors can be extremely useful especially as they are typically non-competitive binders v.s. substrate, but in cases where there is strong mutation selection pressure, on average they are far more easily and quickly defeated by lower fitness-cost mutations then typical active site binding inhibitors.
+Thus, in leu of a really good citation proving this at-face, on-paper, doubly-wrong statement currently made I think this statement should be removed.  Additionally a "really good citation" would be one that actually has data to back up such an assertion instead of such an assertion just dumped into a paper unproven by a protac author who is "selling their wares" with lofty (but unproven) statements as many of us scientific authors are want to do from time to time very much to the discredit of what has become of modern science.[[Special:Contributions/162.220.42.222|162.220.42.222]] ([[User talk:162.220.42.222|talk]]) 18:59, 26 May 2022 (UTC)