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A New Mode of Cancer Treatment

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322 points atomroflbomber | 3 comments | 03 Aug 23 08:12 UTC | HN request time: 0.695s | source
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flobosg ◴[03 Aug 23 09:56 UTC] No.36983634[source]▶
Not a medical chemist, but I noticed that three AOH1996 molecules are binding to PCNA. Would it make sense to chain together three AOH1996 molecules with flexible linkers for, I don't know, increased specificity or something like that?
replies(1): >>36983803 #
irdc ◴[03 Aug 23 10:21 UTC] No.36983803[source]▶
Maybe. But a bigger molecule will be less soluble and less capable of getting into the cell.
replies(1): >>36984202 #
flobosg ◴[03 Aug 23 11:18 UTC] No.36984202[source]▶
Right! I forgot about good ol’ Lipinski: https://en.wikipedia.org/wiki/Lipinski%27s_rule_of_five
replies(2): >>36984970 #>>36986934 #
1. mallomarmeasle ◴[03 Aug 23 12:32 UTC] No.36984970[source]▶
Note that a number of well-known drugs violate Lipinski's rules. For instance, digoxin is absorbed by transporters and violates 2 rules. Atorvastatin is another famous example (again 2 rules violated). I believe that it is absorbed through Peyer's patches in the intestine.

https://www.pmf.ni.ac.rs/chemianaissensis/wp-content/uploads...

replies(2): >>36985009 #>>36991835 #
2. flobosg ◴[03 Aug 23 12:36 UTC] No.36985009[source]▶
Thanks for pointing it out. The Wikipedia article mentions that as well, along with some other examples:

> Some authors have criticized the rule of five for the implicit assumption that passive diffusion is the only important mechanism for the entry of drugs into cells, ignoring the role of transporters.

> Studies have also demonstrated that some natural products break the chemical rules used in Lipinski filters such as macrolides and peptides.

3. panabee ◴[03 Aug 23 21:01 UTC] No.36991835[source]▶
thanks for sharing these exceptions.

key quote from the linked wikipedia article:

This famous "rule of 5" has been highly influential in this regard, but only about 50% of orally administered new chemical entities actually obey it. [5]

[5] O Hagan S, Swainston N, Handl J, Kell DB (2015). "A 'rule of 0.5' for the metabolite-likeness of approved pharmaceutical drugs". Metabolomics. 11 (2): 323–339. doi:10.1007/s11306-014-0733-z. PMC 4342520. PMID 25750602.