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

• DOI: 10.1021/jm031087c
• Publication Date: 2004-03-18T05:37:44Z
• Authors: Claudia Binda; Frantisek Hubálek; Min Li; Yaacov Herzig; Jeffrey Sterling; Dale E. Edmondson; Andrea Mattevi
• Keywords: 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

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.