7K41

Bacterial O-GlcNAcase (OGA) with compound

Summary for 7K41

• Entry DOI: 10.2210/pdb7k41/pdb
• Descriptor: O-GlcNAcase BT_4395, ACETATE ION, 4-(4-methylpiperidin-1-yl)-N-(2-phenylethyl)pyrimidin-2-amine, ... (5 entities in total)
• Functional Keywords: oga, virtual screening, structure based drug design, sbdd, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Escherichia coli K-12
• Total number of polymer chains: 1
• Total formula weight: 83552.48

Authors

Lane, W.,Tjhen, R.,Snell, G.,Sang, B. (deposition date: 2020-09-14, release date: 2021-01-13, Last modification date: 2023-10-18)

Primary citation

Tawada, M.,Fushimi, M.,Masuda, K.,Sun, H.,Uchiyama, N.,Kosugi, Y.,Lane, W.,Tjhen, R.,Endo, S.,Koike, T.
Discovery of a Novel and Brain-Penetrant O -GlcNAcase Inhibitor via Virtual Screening, Structure-Based Analysis, and Rational Lead Optimization.
J.Med.Chem., 64:1103-1115, 2021

PubMed Abstract: -GlcNAcase (OGA) has received increasing attention as an attractive therapeutic target for tau-mediated neurodegenerative disorders; however, its role in these pathologies remains unclear. Therefore, potent chemical tools with favorable pharmacokinetic profiles are desirable to characterize this enzyme. Herein, we report the discovery of a potent and novel OGA inhibitor, compound , comprising an aminopyrimidine scaffold, identified by virtual screening based on multiple methodologies combining structure-based and ligand-based approaches, followed by sequential optimization with a focus on ligand lipophilicity efficiency. This compound was observed to increase the level of -GlcNAcylated protein in cells and display suitable pharmacokinetic properties and brain permeability. Crystallographic analysis revealed that the chemical series bind to OGA via characteristic hydrophobic interactions, which resulted in a high affinity for OGA with moderate lipophilicity. Compound could serve as a useful chemical probe to help establish a proof-of-concept of OGA inhibition as a therapeutic target for the treatment of tauopathies.

PubMed: 33404239
DOI: 10.1021/acs.jmedchem.0c01712

Experimental method

X-RAY DIFFRACTION (2 Å)