Computational Fragment-Based Design Facilitates Discovery of Potent and Selective Monoamine Oxidase‑B (MAO-B) Inhibitor

Parkinson’s
disease (PD) is one of the most common age-related
neurodegenerative diseases. Inhibition of monoamine oxidase-B (MAO-B),
which is mainly found in the glial cells of the brain, may lead to
an elevated level of dopamine (DA) in patients. MAO-B inhibitors have
been used extensively for patients with PD. However, the discovery
of the selective MAO-B inhibitor is still a challenge. In this study,
a computational strategy was designed for the rapid discovery of selective
MAO-B inhibitors. A series of (S)-2-(benzylamino)­propanamide
derivatives were designed. In vitro biological evaluations
revealed that (S)-1-(4-((3-fluorobenzyl)­oxy)­benzyl)­azetidine-2-carboxamide
(C3) was more potent and selective than safinamide, a
promising drug for regulating MAO-B. Further studies revealed that
the selectivity mechanism of C3 was due to the steric
clash caused by the residue difference of Phe208 (MAO-A) and Ile199
(MAO-B). Animal studies showed that compound C3 could
inhibit cerebral MAO-B activity and alleviate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP)-induced dopaminergic neuronal loss.