Computational insights into novel inhibitor indole-heterocycle specific against glycogen phosphorylase isoenzymes interaction mechanism

Abstract

Background: Glycogen phosphorylase (GP) is a potential drug target. As the three subtypes of GP are highly conserved, it is difficult to research their specificity. However, compound 1 inhibits the GP subtypes differently and was studied to aid in designing specific inhibitors. Results: Molecular docking showed that the ligands in GP subtype complexes had some differences in spatial conformation and binding modes, stabilized by polar and nonpolar interactions. The results were confirmed through kinetic experiments, with affinities of -85.230 (brain GP), -73.809 (liver GP) and -66.061 kJ/mol (muscle GP). Conclusion: The study provides insight into the possible reasons for differences in compound 1's inhibitory activity against the GP subtypes and offers guidance in designing target molecules for regulating selectivity among the subtypes.