Computer-Aided Drug Design for Type 2 Diabetes-Related Enzymes: Polarizable and Nonpolarizable Simulations of Enzyme-Inhibitor Complexes

In this study, molecular dynamics (MD) simulations were performed to investigate the stability and interaction patterns of inhibitors identified through SILCS-based virtual screening. Representative ligands for the N-terminal and C-terminal domains of MGAM (NtMGAM, CtMGAM), and α-amylase were parametrized using both the nonpolarizable CHARMM and polarizable Drude force fields based on quantum mechanical (QM) reference data.

MD simulations of the apo enzymes show that their overall structures remain stable, with flexibility primarily localized to regions surrounding the catalytic pockets. Simulations of the enzyme–ligand complexes demonstrate that the ligands remain associated with the binding regions throughout the trajectories. Comparison between the two force fields reveals distinct interaction patterns: CHARMM interactions are largely driven by a small number of dominant contacts, whereas the Drude model captures a more extensive and cooperative interaction network.