Parameters for Irreversible Inactivation of Monoamine Oxidase

0541318 - ÚFCH JH 2022 RIV CH eng J - Článek v odborném periodiku
Ramsay, R R. - Basile, L. - Maniquet, A. - Hagenow, S. - Pappalardo, M. - Saija, Maria Chiara - Bryant, Sharon D. - Albreht, A. - Guccione, S.
Parameters for Irreversible Inactivation of Monoamine Oxidase.
Molecules. Roč. 25, č. 24 (2020), č. článku 5908. E-ISSN 1420-3049
Institucionální podpora: RVO:61388955
Klíčová slova: high-level expression * benzylamine analogs * molecular-dynamics * inhibition * propargylamine * neuroprotection * cholinesterase * oxidation * deprenyl * ligands * fad * irreversible inhibition * enzyme kinetics * computational modeling * pharmacophore * spectrum * adduct
Obor OECD: Physical chemistry
Impakt faktor: 4.412, rok: 2020
Způsob publikování: Open access

The irreversible inhibitors of monoamine oxidases (MAO) slow neurotransmitter metabolism in depression and neurodegenerative diseases. After oxidation by MAO, hydrazines, cyclopropylamines and propargylamines form a covalent adduct with the flavin cofactor. To assist the design of new compounds to combat neurodegeneration, we have updated the kinetic parameters defining the interaction of these established drugs with human MAO-A and MAO-B and analyzed the required features. The K-i values for binding to MAO-A and molecular models show that selectivity is determined by the initial reversible binding. Common to all the irreversible inhibitor classes, the non-covalent 3D-chemical interactions depend on a H-bond donor and hydrophobic-aromatic features within 5.7 angstroms apart and an ionizable amine. Increasing hydrophobic interactions with the aromatic cage through aryl halogenation is important for stabilizing ligands in the binding site for transformation. Good and poor inactivators were investigated using visible spectroscopy and molecular dynamics. The initial binding, close and correctly oriented to the FAD, is important for the oxidation, specifically at the carbon adjacent to the propargyl group. The molecular dynamics study also provides evidence that retention of the allenyl imine product oriented towards FADH(-) influences the formation of the covalent adduct essential for effective inactivation of MAO.
Trvalý link: http://hdl.handle.net/11104/0318893