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

Experimental and theoretical physico-chemical methods were used to investig ate the interaction between several reversible monoamine oxidase A inhibito rs in the oxazolidinone series and the active site of the enzyme. Phenyloxa zolidinones include toloxatone and analogues, among which befloxatone was s elected as drug candidate for the treatment of depression. Identification o f the forces responsible for the crystal cohesion of befloxatone reveals fu nctional 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 befloxaton e and the cofactor of the enzyme. Electronic absorption spectroscopy measur ements confirm the hypothesis of a privileged interaction of phenyloxazolid inone-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 dis tance, reversible interactions with the flavin adenine dinucleotide (FAD) c ofactor of the enzyme and with specific amino acids of the active site. Thi s model is partially corroborated by experimental evidence and should be he lpful in designing new potent inhibitors of monoamine oxidase. (C) 1999 Els evier Science Ltd. All rights reserved.