AMPA Receptor Noncompetitive Inhibitors Occupy a Promiscuous Binding Site

ACS Chem Neurosci. 2019 Nov 20;10(11):4511-4521. doi: 10.1021/acschemneuro.9b00344. Epub 2019 Oct 24.

Abstract

Noncompetitive inhibitors of AMPA receptors have attracted interest in recent years as antiepileptic drugs. However, their development is hindered by a lack of detailed understanding of the protein-inhibitor interaction mechanisms. Recently, structures of AMPA receptor complexes with the structurally dissimilar, noncompetitive, small-molecule inhibitors pyridone perampanel (PMP), GYKI 53655 (GYKI), and CP 465022 (CP) were resolved, revealing that all three share a common binding site. However, due to the low resolution of the ligands, their exact binding modes and protein-ligand interactions remain ambiguous and insufficiently detailed. We carried out molecular dynamics (MD) simulations on X-ray-resolved and docked AMPA receptor complexes, including thermodynamic integration (TI) to compute ligand binding constants, in order to investigate the inhibitor binding modes in detail and identify key protein-ligand interaction mechanisms. Our analysis and simulations show that the ligand binding pocket at the interface of the receptor's transmembrane domain exhibits features also found in the binding pockets of the multidrug-resistance proteins. The inhibitors bind to such promiscuous pockets by forming multiple weak contacts, while the large, flexible pocket undergoes adjustments to accommodate structurally different ligands in different orientations. TI was able to identify a specific more favorable binding mode for GYKI, while PMP, which has a symmetric ring structure, produced several comparable poses indicating that it may bind in several orientations.

Keywords: AMPA receptors; CP 465022; GYKI 53655; molecular dynamics simulations; noncompetitive inhibitors; perampanel.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Binding Sites
  • Membranes, Artificial
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Phosphatidylcholines
  • Receptors, AMPA / antagonists & inhibitors*
  • Receptors, AMPA / chemistry
  • Receptors, AMPA / metabolism
  • Water

Substances

  • Membranes, Artificial
  • Phosphatidylcholines
  • Receptors, AMPA
  • Water
  • 1-palmitoyl-2-oleoylphosphatidylcholine