Computational predictions of binding affinities to dihydrofolate reductase: synthesis and biological evaluation of methotrexate analogues.
J Med Chem
; 43(21): 3852-61, 2000 Oct 19.
Article
em En
| MEDLINE
| ID: mdl-11052790
ABSTRACT
The relative binding affinities to human dihydrofolate reductase of four new potential antifolates, containing ester linkages between the two aromatic systems, were estimated by free energy perturbation simulations. The ester analogue, predicted to exhibit the highest binding affinity to human dihydrofolate reductase, and a reference ester (more structurally related to methotrexate) were synthesized. As deduced from the measured IC(50) values, the calculated ranking of the ligands was correct although a greater difference in affinity was indicated by the experimental measurements. Among the new antifolates the most potent inhibitor exhibited a similar pharmacokinetic profile to methotrexate but lacked activity in a complex antiarthritic model in rat in vivo.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tetra-Hidrofolato Desidrogenase
/
Metotrexato
/
Antagonistas do Ácido Fólico
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2000
Tipo de documento:
Article
País de afiliação:
Suécia