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Computer-aided drug design: A free energy perturbation study on the binding of methyl-substituted pterins and N5-deazapterins to dihydrofolate reductase (1993)

Cummins, Peter L. ; Gready, Jill E.

Springer

Journal of computer aided molecular design 7 (1993), S. 535-555

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ISSN: 1573-4951

Keywords: Molecular dynamics ; Thermodynamics ; Hydration ; Ligand-protein interactions

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Summary Molecular dynamics simulation and free energy perturbation techniques have been used to study the relative binding free energies of 8-methylpterins and 8-methyl-N5-deazapterins to dihydrofolate reductase (DHFR). Methyl-substitution at the 5, 6 and 7 positions in the N-heterocyclic ring gives rise to a variety of ring substituent patterns and biological activity: several of these methyl derivatives of the 8-methyl parent compounds (8-methylpterin and 8-methyl-N5-deazapterin) have been identified as substrates or inhibitors of vertebrate DHFR in previous work. The calculated free energy differences reveal that the methyl-substituted compounds are thermodynamically more stable than the primary compounds (8-methylpterin and 8-methyl-N5-deazapterin) when bound to the enzyme, due largely to hydrophobic hydration phenomena. Methyl substitution at the 5 and/or 7 positions in the 6-methyl-substituted compounds has only a small effect on the stability of ligand binding. Furthermore, repulsive interactions between the 6-methyl substituent and DHFR are minimal, suggesting that the 6-methyl position is optimal for binding. The results also show that similarly substituted 8-methylpterins and 8-methyl-N5-deazapterins have very similar affinities for binding to DHFR. The computer simulation predictions are in broad agreement with experimental data obtained from kinetic studies, i.e. 6,8-dimethylpterin is a more efficient substrate than 8-methylpterin and 6,8-dimethyl-N5-deazapterin is a better inhibitor than 8-methyl-N5-deazapterin.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF00124361

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Novel mechanism-based substrates of dihydrofolate reductase and the thermodynamics of ligand binding: A comparison of theory and experiment for 8-methylpterin and 6,8-dimethylpterin (1993)

Cummins, Peter L. ; Gready, Jill E.

New York, NY : Wiley-Blackwell

Proteins: Structure, Function, and Genetics 15 (1993), S. 426-435

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ISSN: 0887-3585

Keywords: molecular dynamics ; free energy ; perturbation theory ; kinetic mechanism ; dissociation constants ; dihydrofolate reductase ; 8-methyl-pterins ; Chemistry ; Biochemistry and Biotechnology

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Medicine

Notes: Molecular dynamics simulation and free energy perturbation techniques have been used to study the relative binding free energies of the designed mechanism-based pterins, 8-methylpterin and 6,8-dimethylpterin, to dihydrofolate reductase (DHFR), with co-factor nicotinamide adenine dinucleotide phosphate (NADPH). The calculated free energy differences suggest that DHFR.NADPH.6,8-dimethylpterin is thermodynamically more stable than DHFR.NADPH.8-methylpterin by 2.4 kcal/mol when the substrates are protonated and by 1.3 kcal/mol when neutral. The greater binding strength of 6,8-dimethylpterin may be attributed largely to hydration effects. In terms of an appropriate model for the pH-dependent kinetic mechanism, these differences can be interpreted consistently with experimental data obtained from previous kinetic studies, i.e., 6,8-dimethylpterin is a more efficient substrate of vertebrate DHFRs than 8-methylpterin. The kinetic data suggest a value of 6.6 ± 0.2 for the pKa of the active site Glu-30 in DHFR.NADPH. We have also used experimental data to estimate absolute values for thermodynamic dissociation constants of the active (i.e., protonated) forms of the substrates: these are of the same order as for the binding of folate (0.1-10 μM). The relative binding free energy calculated from the empirically derived dissociation constants for the protonated forms of 8-methylpterin and 6,8-dimethylpterin is 1.4 kcal/mol, a value which compares reasonably well with the theoretical value of 2.4 kcal/mol. © 1993 Wiley-Liss, Inc.

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