molecules of the month

“compound 5i”

oral, brain-penetrant O-GlcNAcase (OGA) inh.

structurally distinct in vivo tool

from virtual screen of 100k cmpd, testing 2681

J. Med. Chem., Jan. 6, 2021

Takeda Pharmaceutical, Fujisawa, JP

Chemical structure of compound-5i Takeda O-GlcNAcase (OGA) inhibitor
1 min read

The Takeda O-GlcNAcase (OGA) inhibitor, “compound 5i,” binds to the same site as prior sugar-based OGA inhibitors, but has surprisingly different chemical properties and a unique binding mode. The Takeda team realized that polar, sugar-based OGA inhibitors would be challenging to get into the brain where they would be needed for neurodegenerative diseases, and so used an elegant virtual-screening and structure-based approach to make the leap to the distinct, CNS-friendly starting point for compound 5i. The less basic pyrimidine N(1) nitrogen (pKa ~ 4.9) surprisingly appears to be protonated in the binding site, making a bidentate interaction with a carboxylate, likely helped by the presence of a second Asp residue. The article is a great case-study for identifying distinct new…

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