Glycogen Phosphorylase Inhibitors: A Free Energy Perturbation Analysis of Glucopyranose Spirohydantoin Analogues

ABSTRACT GP catalyzes the phosphorylation of glycogen to Glc-1-P. Because of its fundamental role in the metabolism of glycogen, GP has been the target for a systematic structure-assisted design of inhibitory compounds, which could be of value in the therapeutic treatment of type 2 diabetes melli-tus. The most potent catalytic-site inhibitor of GP identified to date is spirohydantoin of glucopyr-anose (hydan). In this work, we employ MD free energy simulations to calculate the relative binding affinities for GP of hydan and two spirohydantoin analogues, methyl-hydan and n-hydan, in which a hydrogen atom is replaced by a methyl- or amino group, respectively. The results are compared with the experimental relative affinities of these ligands