Synthesis, evaluation and structural investigations of potent purple acid phosphatase inhibitors as drug leads for osteoporosis.
Eur J Med Chem
; 182: 111611, 2019 Nov 15.
Article
en En
| MEDLINE
| ID: mdl-31445230
ABSTRACT
Purple acid phosphatases (PAPs) are binuclear hydrolases that catalyze the hydrolysis of phosphorylated substrates under acidic to neutral conditions. Elevated serum concentrations of PAP are observed in patients suffering from osteoporosis, identifying this enzyme as a potential target for the development of novel therapeutic agents to treat this disease. α-Alkoxy-substituted naphthylmethylphosphonic acid derivatives have been identified previously as molecules that bind with high affinity to PAPs, and docking studies suggest that longer alkyl chains may increase the binding affinities of such compounds. Here, we synthesized several derivatives and tested their inhibitory effect against pig and red kidney bean PAPs. The most potent inhibitor within this series is the octadecyl derivative, which has a Ki value of â¼200â¯nM. Crystal structures of the dodecyl and octadecyl derivatives bound to red kidney bean PAP show that the length of the alkyl chain influences the ability of the phosphonate group to interact directly with the bimetallic center. These structures represent the first examples of potent inhibitors bound to a PAP that have drug-like properties. This study provides a starting point for the development of much needed new treatments for osteoporosis.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Osteoporosis
/
Fosfatasa Ácida
/
Inhibidores Enzimáticos
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Eur J Med Chem
Año:
2019
Tipo del documento:
Article
País de afiliación:
Australia
Pais de publicación:
FR
/
FRANCE
/
FRANCIA
/
FRANÇA