Molecular dynamics simulations of the docking of substituted N5- deazapterins to dihydrofolate reductase

• DOI: 10.1093/protein/10.1.23
• Publication Date: 2002-07-26T22:32:47Z
• Authors: A. D. Gorse; J. E. Gready
• Keywords: Dihydrofolate reductase; Docking (animal); Binding affinities; Affinities; Dissociation constant; Thermodynamic integration

Orientations of the deazapterin ring and conformational preferences groups appended to in a set 8-substituted cations docked into dihydrofolate reductase (DHFR) binding site have been investigated using methodology based on simulated annealing technique within molecular dynamics (MD) simulations. Of five possible pockets for 8-substituents, identified from preliminary manual docking study, one has definitively eliminated after an analysis MD trajectories, while another remains uncertain. Using new method standard thermodynamic cycles linear approximation polar non-polar free energy contributions averages, affinities different ligands each correlated with experimental dissociation constants. The study provided insights structure-activity relationships use design modified inhibitors DHFR.