5QJ3

CRYSTAL STRUCTURE OF MYELOPEROXIDASE SUBFORM C (MPO) COMPLEX WITH COMPOUND-24 AKA 7-({4-CHLORO-3'-FLUORO-[1,1'- BIPHENYL]-3-YL}METHOXY)-3H-[1,2,3]TRIAZOLO[4,5-B]PYRIDIN- 5-AMINE

Summary for 5QJ3

• Entry DOI: 10.2210/pdb5qj3/pdb
• Group deposition: MPO (G_1002056)
• Descriptor: Myeloperoxidase, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (10 entities in total)
• Functional Keywords: myeloperoxidase, metal binding protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 135686.33

Authors

Khan, J.A. (deposition date: 2018-09-26, release date: 2019-02-06, Last modification date: 2024-10-30)

Primary citation

Wurtz, N.R.,Viet, A.,Shaw, S.A.,Dilger, A.,Valente, M.N.,Khan, J.A.,Jusuf, S.,Narayanan, R.,Fernando, G.,Lo, F.,Liu, X.,Locke, G.A.,Kopcho, L.,Abell, L.M.,Sleph, P.,Basso, M.,Zhao, L.,Wexler, R.R.,Duclos, F.,Kick, E.K.
Potent Triazolopyridine Myeloperoxidase Inhibitors.
ACS Med Chem Lett, 9:1175-1180, 2018

PubMed Abstract: Myeloperoxidase (MPO) generates reactive oxygen species that potentially contribute to many chronic inflammatory diseases. A recently reported triazolopyrimidine MPO inhibitor was optimized to improve acid stability and remove methyl guanine methyl transferase (MGMT) activity. Multiple synthetic routes were explored that allowed rapid optimization of a key benzyl ether side chain. Crystal structures of inhibitors bound to the MPO active site demonstrated alternate binding modes and guided rational design of MPO inhibitors. Thioether showed significant inhibition of MPO activity in an acute mouse inflammation model after oral dosing.

PubMed: 30613322
DOI: 10.1021/acsmedchemlett.8b00308

Experimental method

X-RAY DIFFRACTION (2.76 Å)