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Computational predictions of binding affinities to dihydrofolate reductase: synthesis and biological evaluation of methotrexate analogues.

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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Graffner-Nordberg M,Marelius J,Ohlsson S,Persson A,Swedberg G,Andersson P,Andersson SE,Aqvist J,Hallberg A

doi

10.1021/jm0009639

keywords:

subject

Has Abstract

pub_date

2000-10-19 00:00:00

pages

3852-61

issue

21

eissn

0022-2623

issn

1520-4804

pii

jm0009639

journal_volume

43

pub_type

杂志文章

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