Computational Fragment-Based Design Facilitates Discovery of Potent and Selective Monoamine Oxidase-B (MAO-B) Inhibitor.
J Med Chem
; 63(23): 15021-15036, 2020 12 10.
Article
em En
| MEDLINE
| ID: mdl-33210537
ABSTRACT
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doença de Parkinson Secundária
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Benzilaminas
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Amidas
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Monoaminoxidase
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Inibidores da Monoaminoxidase
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2020
Tipo de documento:
Article