title: Molecular dynamics simulations of the docking of substituted N5-deazapterins to dihydrofolate reductase.
abstract: Orientations of the deazapterin ring and the conformational preferences of groups appended to the deazapterin ring in a set of 8-substituted deazapterin cations docked into the dihydrofolate reductase (DHFR) binding site have been investigated using a methodology based on the simulated annealing technique within molecular dynamics (MD) simulations. Of five possible binding pockets for the 8-substituents, identified from a preliminary manual docking study, one has been definitively eliminated after an analysis of MD trajectories, while another remains uncertain. Using a new method based on standard thermodynamic cycles and a linear approximation of polar and non-polar free energy contributions from MD averages, binding affinities of the different ligands in each binding site have been correlated with experimental dissociation constants. The study has provided insights into structure-activity relationships for use in the design of modified inhibitors of DHFR.
authors.affiliation: Division of Biochemistry and Molecular Biology, John Curtin School of Medical Research, Australian National University, Canberra.
authors.forename: A D
authors.initials: AD
authors.lastname: Gorse
authors.forename: J E
authors.initials: JE
authors.lastname: Gready
mesh_terms: D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D005493:Folic Acid Antagonists / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding / Q000502:physiology; D011487:Protein Conformation; D011622:Pterins / Q000737:chemistry*; D012044:Regression Analysis; D013329:Structure-Activity Relationship; D013696:Temperature; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000187:drug effects* / Q000494:pharmacology; D013816:Thermodynamics
chemical_list: C085591:6,8-dimethyl-N(5)-deazapterin; D005493:Folic Acid Antagonists; D008024:Ligands; D011622:Pterins; D013762:Tetrahydrofolate Dehydrogenase