Computational predictions of binding affinities to dihydrofolate reductase: synthesis and biological evaluation of methotrexate analogues
(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:
https://lup.lub.lu.se/record/1118392
- author
- Graffner-Nordberg, M ; Marelius, J ; Ohlsson, S ; Persson, A ; Swedberg, G ; Andersson, P ; Andersson, Sven LU ; Aqvist, J and Hallberg, A
- organization
- publishing date
- 2000
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Medicinal Chemistry
- volume
- 43
- issue
- 21
- pages
- 3852 - 3861
- publisher
- The 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
- 2016-04-01 12:26:39
- date last changed
- 2024-01-08 20:41:27
@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 = {{The 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}},
doi = {{10.1021/jm0009639}},
volume = {{43}},
year = {{2000}},
}