A reversible monoamine oxidase a inhibitor, befloxatone: Structural approach of its mechanism of action

Johan Wouters, Florence Moureau, Guy Evrard, Jean Jacques Koenig, Samir Jegham, Pascal George, François Durant

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Résumé

Experimental and theoretical physico-chemical methods were used to investigate the interaction between several reversible monoamine oxidase A inhibitors in the oxazolidinone series and the active site of the enzyme. Phenyloxazolidinones include toloxatone and analogues, among which befloxatone was selected as drug candidate for the treatment of depression. Identification of the forces responsible for the crystal cohesion of befloxatone reveals functional groups that could interact with monoamine oxidase. Calculation of electronic properties of those compounds using ab initio molecular orbital methods lead to a description of the mode of interaction between befloxatone and the cofactor of the enzyme. Electronic absorption spectroscopy measurements confirm the hypothesis of a privileged interaction of phenyloxazolidinone-type inhibitors with the flavin cofactor of MAO. Additional sites of interaction with the protein core of MAO A are also examined with regard to the primary structure of the enzyme. As a result of this work, a model is proposed for the reversible inhibition of MAO A by befloxatone via long distance, reversible interactions with the flavin adenine dinucleotide (FAD) cofactor of the enzyme and with specific amino acids of the active site. This model is partially corroborated by experimental evidence and should be helpful in designing new potent inhibitors of monoamine oxidase. Copyright (C) 1999 Elsevier Science Ltd.

langue originaleAnglais
Pages (de - à)1683-1693
Nombre de pages11
journalBioorganic and Medicinal Chemistry
Volume7
Numéro de publication8
Les DOIs
Etat de la publicationPublié - 1 août 1999

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