MOLECULAR-DYNAMICS SIMULATIONS OF THE DOCKING OF SUBSTITUTED N5-DEAZAPTERINS TO DIHYDROFOLATE-REDUCTASE

Orientations of the deazapterin ring and the conformational preference s of groups appended to the deazapterin ring in a set of 8-substituted deazapterin cations docked into the dihydrofolate reductase (DHFR) bi nding site have been investigated using a methodology based on the sim ulated annealing technique within molecular dynamics (MD) simulations. Of five possible binding pockets for the 8-substituents, identified f rom a preliminary manual docking study, one has been definitively elim inated after an analysis of MD trajectories, while another remains unc ertain. Using a new method based on standard thermodynamic cycles and a linear approximation of polar and non-polar free energy contribution s from MD averages, binding affinities of the different ligands in eac h binding site have been correlated with experimental dissociation con stants, The study has provided insights into structure-activity relati onships for use in the design of modified inhibitors of DHFR.