Mechanistic insights into protonation state as a critical factor in hFPPS enzyme inhibition.
J Comput Aided Mol Des
; 29(7): 667-80, 2015 Jul.
Article
em En
| MEDLINE
| ID: mdl-26081258
ABSTRACT
Zoledronate and risedronate are the most powerful available nitrogen-containing bisphosphonates used in the treatment of bone-resorption disorders. Knowledge about inhibition mechanisms of these molecules is based on available crystallographic structures of human farnesyl pyrophosphate synthase (hFPPS). However, there is a lack of information explaining the inhibition potency of these two molecules compared to the natural substrate, dimethylallyl pyrophosphate. We carried out a molecular dynamics study that shown (1) that NBPs potency is related to higher electrostatic interactions with the metallic cluster of the active site than to the natural substrate, and (2) the protonation of the R2 side chain is a critical factor to stabilize the NBPs into a closely irreversible ternary complex with the hFPPS.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Inibidores Enzimáticos
/
Geraniltranstransferase
Limite:
Humans
Idioma:
En
Revista:
J Comput Aided Mol Des
Assunto da revista:
BIOLOGIA MOLECULAR
/
ENGENHARIA BIOMEDICA
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Espanha