title: 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.
authors.affiliation: Department of Biochemistry, University of Sydney, N.S.W., Australia.
authors.forename: P L
authors.initials: PL
authors.lastname: Cummins
authors.forename: J E
authors.initials: JE
authors.lastname: Gready
mesh_terms: D000818:Animals; D001665:Binding Sites; D002645:Chickens; D003198:Computer Simulation; D015195:Drug Design; D066298:In Vitro Techniques; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D011622:Pterins / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D011622:Pterins; D013762:Tetrahydrofolate Dehydrogenase