title: Mapping the binding of GluN2B-selective N-methyl-D-aspartate receptor negative allosteric modulators.
abstract: We have used recent structural advances in our understanding of the N-methyl-d-aspartate (NMDA) receptor amino terminal domain to explore the binding mode of multiple diaryl GluN2B-selective negative allosteric modulators at the interface between the GluN1 and GluN2B amino-terminal domains. We found that interaction of the A ring within the binding pocket seems largely invariant for a variety of structurally distinct ligands. In addition, a range of structurally diverse linkers between the two aryl rings can be accommodated by the binding site, providing a potential opportunity to tune interactions with the ligand binding pocket via changes in hydrogen bond donors, acceptors, as well as stereochemistry. The most diversity in atomic interactions between protein and ligand occur in the B ring, with functional groups that contain electron donors and acceptors providing additional atomic contacts within the pocket. A cluster of residues distant to the binding site also control ligand potency, the degree of inhibition, and show ligand-induced increases in motion during molecular dynamics simulations. Mutations at some of these residues seem to distinguish between structurally distinct ligands and raise the possibility that GluN2B-selective ligands can be divided into multiple classes. These results should help facilitate the development of well tolerated GluN2B subunit-selective antagonists.
authors.affiliation: Department of Chemistry, Emory University, 1515 Dickey Dr., Atlanta, GA 30302, USA. pieter.burger@gmail.com
authors.forename: Pieter B
authors.initials: PB
authors.lastname: Burger
authors.forename: Hongjie
authors.initials: H
authors.lastname: Yuan
authors.forename: Erkan
authors.initials: E
authors.lastname: Karakas
authors.forename: Matthew
authors.initials: M
authors.lastname: Geballe
authors.forename: Hiro
authors.initials: H
authors.lastname: Furukawa
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Traynelis
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000235:genetics; D000818:Animals; D005260:Female; D008024:Ligands; D051379:Mice; D056004:Molecular Dynamics Simulation; D010880:Piperidines / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding / Q000235:genetics; D025941:Protein Interaction Mapping / Q000379:methods; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry* / Q000172:deficiency / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D008024:Ligands; C121001:NR2B NMDA receptor; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C010739:ifenprodil