Structure based virtual screening of novel noncompetitive antagonist of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor.

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype ionotropic glutamate receptors are attractive antiepileptic targets responsible for mediating the majority of excitatory neurotransmission and plasticity. The noncompetitive antagonists obtain more and more attention as drug candidates for treatment of the neurological diseases involving excessive activity of AMPARs, due to they regulate AMPA receptors (AMPARs) activity independently of endogenous glutamate levels unlike the competitive antagonists. Development of novel AMPAR noncompetitive antagonists, which are safer and more efficacious than competitive antagonists, is highly under demand. Here, we present the discovery of novel antagonists against AMPAR through Structure-Based Virtual Screening (SBVS). Three compounds were successfully distinguished by several different filtering strategies, namely STOCK6S-10902, STOCK1N-49134 and STOCK5S-68665. The interaction mode of these compounds was further explored through molecular dynamics simulation, binding free energy calculation and the binding free energy decomposition. It is demonstrated that some residues within the binding pocket, which have been proved their importance in antagonist binding and gating, form strong hydrogen bond interactions with these three molecules. In particular, H-bond interactions with high occupancies between Ser516, Ser788 and STOCK6S-10902 and Ser516, Asn791 and STOCK1N-49134 were observed. The three hit compounds with new scaffolds and the detailed binding modes could potentially serve as a starting point for further optimization and development.