Computational Characterization of the Binding of Non-Competitive Inhibitors to AMPA Receptors

Abstract

Non-competitive inhibitors of AMPA receptors have attracted significant interest in the recent years as potential antiepileptic drugs. While a considerable number of small molecules have been identified and tested as AMPA receptor non-competitive antagonists, only pyridone perampanel (PMP) has been approved for clinical use as an antiepileptic drug. PMP, however, still causes side effects at higher doses, indicating the need for safer and more effective drugs. Recently resolved crystal structures of AMPA receptor complexes of GYKI 53655 (GYKI), CP 465022 (CP), and PMP provided new structural information on non-competitive inhibitor binding to AMPA receptors. While these structurally dissimilar inhibitors share a common binding site, each ligand interacts differently with individual amino acid residues in the binding pocket. However, due to the limited resolution of the crystal structures they do not provide a comprehensive atomistic picture of specific protein-ligand interactions that are important in inhibitor binding. In this study, molecular docking along with molecular dynamics (MD) simulations and binding energy calculations were carried out to assess the stability of crystallographically determined binding modes and explore potential alternative binding modes of inhibitors GYKI, CP, and PMP. Our MD simulation results provide structural insights into interactions of these inhibitors with AMPA receptors and highlight the features of the AMPA receptor non-competitive inhibitor binding pocket that are important in accommodating structurally different inhibitors. This information will aid in structure-based design of new non-competitive inhibitors that target AMPA receptors.