Crystal Structures of Monoamine Oxidase B in Complex with Four Inhibitors of theN-Propargylaminoindan Class

drug-design Models, Molecular 570 0303 health sciences Binding Sites Monoamine Oxidase Inhibitors Molecular Structure neurology Stereoisomerism 540 Crystallography, X-Ray 3. Good health Kinetics Structure-Activity Relationship 03 medical and health sciences Alkynes Indans Parkinson Monoamine Oxidase
DOI: 10.1021/jm031087c Publication Date: 2004-03-18T05:37:44Z
ABSTRACT
Monoamine oxidase B (MAO B) is an outer mitochondrial membrane enzyme that catalyzes the oxidation of arylalkylamine neurotransmitters. The crystal structures of MAO B in complex with four of the N-propargylaminoindan class of MAO covalent inhibitors (rasagiline, N-propargyl-1(S)-aminoindan, 6-hydroxy-N-propargyl-1(R)-aminoindan, and N-methyl-N-propargyl-1(R)-aminoindan) have been determined at a resolution of better than 2.1 A. Rasagiline, 6-hydroxy-N-propargyl-1(R)-aminoindan, and N-methyl-N-propargyl-1(R)-aminoindan adopt essentially the same conformation with the extended propargyl chain covalently bound to the flavin and the indan ring located in the rear of the substrate cavity. N-Propargyl-1(S)-aminoindan binds with the indan ring in a flipped conformation with respect to the other inhibitors, which causes a slight movement of the Tyr326 side chain. Four ordered water molecules are an integral part of the active site and establish H-bond interactions to the inhibitor atoms. These structural studies may guide future drug design to improve selectivity and efficacy by introducing appropriate substituents on the rasagiline molecular scaffold.
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