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

Abstract

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.

Computational Predictions of Binding Affinities to Dihydrofolate Reductase: Synthesis and Biological Evaluation of Methotrexate Analogues

“…Relative binding affinities were calculated as relative free energies of binding using the free energy perturbation (FEP) method . For another application of this method to DHFR inhibitors, see Cummins and Gready .…”

Computational Studies of Difference in Binding Modes of Peptide and Non-Peptide Inhibitors to MDM2/MDMX Based on Molecular Dynamics Simulations

“…To date, several effective methods have been proposed to calculate the binding free energies of protein inhibitors: free energy perturbation (FEP) [35], thermodynamic integration (TI) [36,37] and MM-PB(GB)SA etc. [21,38–41].…”

A computational analysis of interaction mechanisms of peptide and non-peptide inhibitors with MDMX based on molecular dynamics simulation

“…now, several effective methods have been proposed to calculate the binding free energies of inhibitors to proteins: free energy perturbation (FEP) [29], thermodynamic integration (TI) [30,31] and MM-GBSA method [32][33][34]. Although FEP and TI should give more accurate binding free energies, they are restricted to closely related chemical structures of small molecules.…”