| 1. |
- Graffner-Nordberg, Malin, et al.
(författare)
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Computational predictions of binding affinities to dihydrofolate reductase: synthesis and biological evaluation of methotrexate analogues
- 2000
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 43:21, s. 3852-3861
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Tidskriftsartikel (refereegranskat)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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| 2. |
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| 3. |
- Ljungberg, Kajsa B, et al.
(författare)
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Computational Modelling of Inhibitor Binding to Human Thrombin
- 2001
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Ingår i: Eur. J. Pharm. Sci.. ; 12:4, s. 441-446
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Tidskriftsartikel (refereegranskat)abstract
- Thrombin is an essential protein involved in blood clot formation and an important clinical target, since disturbances of the coagulation process cause serious cardiovascular diseases such as thrombosis. Here we evaluate the performance of a molecular dynamics based method for predicting the binding affinities of different types ofhuman thrombin inhibitors. Far a series of eight ligands the method ranks their relative affinities reasonably well. The binding free energy difference between high and low affinity representatives in the test set is quantitatively reproduced, as well as the stereospecificity for a chiral inhibitor. The original parametrisation of this linear interaction energy method requires the addition of a constant energy term in the case of thrombin. This yields a mean unsigned error of 0.68 kcal/mol for the absolute binding free energies. This type of approach is also useful for elucidating three-dimensional structure-activity relationships in terms ofmicroscopic interactions of the ligands with the solvated enzyme.
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| 4. |
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| 5. |
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| 6. |
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| 7. |
- Marelius, J., Kolmodin, K., et al.
(författare)
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Q Manual for Version 4
- 2000
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Annan publikation (övrigt vetenskapligt/konstnärligt)
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| 8. |
- Marelius, J., et al.
(författare)
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Sensitivity of an Empirical Affinity Scoring Function to Changes in Receptor-Ligand Complex Conformations
- 2001
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Ingår i: European Journal of Pharmaceutical Sciences. - 0928-0987 .- 1879-0720. ; 14:1, s. 87-95
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Tidskriftsartikel (refereegranskat)abstract
- A combination of empirical scoring and conformational sampling for ligand bindingaffinity prediction is examined. The behaviour of a scoring function with respect to thesensitivity to conformational changes is investigated using ensembles of structures generated by molecular dynamics simulation. The correlation between the calculated score and the coordinate deviation from the experimental structure is clear for the complex of arabinose with arabinose-binding protein, which is dominated by hydrogen bond interactions, while the score calculated for the hydrophobic complex between retinol and retinol binding protein is rather insensitive to ligand conformational changes. For typical ensembles of stuctures generated by molecular dynamics at 300 K. the variation of the calculated score is considerably smaller than that of the underlying molecular mechanics interaction energies.
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| 9. |
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| 10. |
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