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

Graffner-Nordberg, M; Marelius, J; Ohlsson, S; Persson, A; Swedberg, G; Andersson, P; Andersson, Sven LU ; Aqvist, J and Hallberg, A (2000) In Journal of Medicinal Chemistry 43(21). p.3852-3861
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Medicinal Chemistry
volume
43
issue
21
pages
3852 - 3861
publisher
American Chemical Society (ACS)
external identifiers
  • pmid:11052790
  • scopus:0034687230
ISSN
1520-4804
DOI
10.1021/jm0009639
language
English
LU publication?
yes
id
4d15d6e8-c512-4936-a835-2c7b6658843e (old id 1118392)
date added to LUP
2008-06-16 14:44:03
date last changed
2017-07-30 03:50:41
@article{4d15d6e8-c512-4936-a835-2c7b6658843e,
  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.},
  author       = {Graffner-Nordberg, M and Marelius, J and Ohlsson, S and Persson, A and Swedberg, G and Andersson, P and Andersson, Sven and Aqvist, J and Hallberg, A},
  issn         = {1520-4804},
  language     = {eng},
  number       = {21},
  pages        = {3852--3861},
  publisher    = {American Chemical Society (ACS)},
  series       = {Journal of Medicinal Chemistry},
  title        = {Computational predictions of binding affinities to dihydrofolate reductase: synthesis and biological evaluation of methotrexate analogues},
  url          = {http://dx.doi.org/10.1021/jm0009639},
  volume       = {43},
  year         = {2000},
}