9FJT

Human Monoamine Oxidase B in complex with MC4762 inhibitor (9a) at 1.4 A resolution

This is a non-PDB format compatible entry.

Summary for 9FJT

• Entry DOI: 10.2210/pdb9fjt/pdb
• Descriptor: Amine oxidase [flavin-containing] B, FLAVIN-ADENINE DINUCLEOTIDE, N-DODECYL-N,N-DIMETHYL-3-AMMONIO-1-PROPANESULFONATE, ... (5 entities in total)
• Functional Keywords: mao, amine oxidase, oxidase, flavoprotein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 120802.68

Authors

Gottinger, A.,Binda, C. (deposition date: 2024-05-31, release date: 2025-03-12)

Primary citation

Noce, B.,Marchese, S.,Massari, M.,Lambona, C.,Reis, J.,Fiorentino, F.,Raucci, A.,Fioravanti, R.,Casteloa, M.,Mormino, A.,Garofalo, S.,Limatola, C.,Basile, L.,Gottinger, A.,Binda, C.,Mattevi, A.,Mai, A.,Valente, S.
Design of Benzyl-triazolopyrimidine-Based NADPH Oxidase Inhibitors Leads to the Discovery of a Potent Dual Covalent NOX2/MAOB Inhibitor.
J.Med.Chem., 2025

PubMed Abstract: NADPH oxidases (NOXs) are enzymes dedicated to reactive oxygen species (ROS) production and are implicated in cancer, neuroinflammation, and neurodegenerative diseases. VAS2870 is a covalent inhibitor of mainly NOX2 and NOX5. It alkylates a conserved active-site cysteine, blocking productive substrate binding. To enhance potency and selectivity toward NOXs, we conducted some chemical modifications, leading to the discovery of compound that preferentially inhibits NOX2 with an IC of 0.155 μM, and only upon its preactivation. We found that , bearing a pargyline moiety, is also able to selectively inhibit MAOB over MAOA (465-fold) with an IC of 0.182 μM, being the first-in-class dual NOX2/MAOB covalent inhibitor. Tested in the BV2 microglia neuroinflammation model, decreased ROS production and downregulated proinflammatory cytokines as iNOS, IL-1β, and IL-6 expression more efficiently than the single target inhibitors (rasagiline for MAOB and VAS2870 for NOXs) but also, more importantly, than their combination.

PubMed: 40042998
DOI: 10.1021/acs.jmedchem.4c02644

Experimental method

X-RAY DIFFRACTION (1.4 Å)