Irreversible Inhibition of Monoamine Oxidase B by the Antiparkinsonian Medicines Rasagiline and Selegiline: A Computational Study

Abstract We used quantum‐chemical methods to study seven possible mechanisms of monoamine oxidase (MAO) inhibition by acetylenic inhibitors, considering neutral, cationic, anionic and radical mechanisms. MAO is a flavoenzyme responsible for the metabolism of the important neurotransmitters noradrenaline, serotonin and dopamine. It exists in two isoforms: MAO A and MAO B. Selective MAO A inhibitors are used in the treatment of depression, whereas selective MAO B inhibitors such as rasagiline and selegiline are used to relieve symptoms of Parkinson disease. Rasagiline and selegiline are irreversible MAO B inhibitors, each forming a covalent bond with the enzyme's flavin adenine dinucleotide (FAD) cofactor upon inhibition. Although widely used, they both exhibit numerous adverse effects. Our calculations, performed at the B3LYP/6‐311++G(2d,2p)//B3LYP/6‐31+G(d) level of theory, with application of the CPCM solvent reaction field with ϵ = 4 to mimic the polar environment, found that a polar anionic mechanism, involving deprotonation of the inhibitor molecule at the terminal acetylene carbon atom, is the most plausible. The calculated free energies of activation for rasagiline and selegiline by this mechanistic pathway are 19.9 and 23.7 kcal mol–1, respectively, in very good agreement withexperimentally determined values of 20.8 and 21.3 kcal mol–1,respectively. Together with additional experimental and theoretical work, the results presented here could lead to better understanding of the nature of MAO inhibition and possible design of new antiparkinsonians as improved MAO B inhibitors. Some ideas on the strategy to achieve that and perspectives for future work are also given.