Structure–Activity Relationships of Glycogen Phosphorylase Inhibitor FR258900 and Its Analogues: A Combined Synthetic, Enzyme Kinetics, and Computational Study

Abstract

AbstractA series of O‐ or N‐cinnamoylated, p‐coumaroylated, feruloylated, phenyl, and substituted phenylpropiolated derivatives of L‐malic, 3‐hydroxypentanedioic, and L‐glutamic acids were synthesized as analogues of the natural product glycogen phosphorylase (GP) inhibitor FR258900 (2,3‐bis(4‐hydroxycinnamoyloxy)glutaric acid). These compounds proved practically inactive against rabbit muscle glycogen phosphorylase b. A structure–activity study involving previously synthesized tartaric acid analogues of FR258900 revealed that two acyl moieties must be present in the compounds to make a good inhibitor. Molecular modeling methods (docking and quantitative structure–activity relationship (QSAR) calculations) were used to understand the nature of the binding affinities of these GP inhibitors. The generated 3D models for GP–inhibitor complexes showed that both the polar allosteric site pocket and the hydrophobic pocket at the interface of the homodimeric units of GP were important for effective binding of the acyl and aromatic moieties of the inhibitors. The predictive QSAR models consist of empirical and quantum mechanics descriptors and provide good explanatory and predictive abilities (prediction coefficient Q2=0.7–0.9 when cross‐validation procedures were performed).