title: Homology modeling of NR2B modulatory domain of NMDA receptor and analysis of ifenprodil binding.
abstract: NMDA receptors are glutamate-gated ion channels (iGluRs) that are involved in several important physiological functions such as neuronal development, synaptic plasticity, learning, and memory. Among iGluRs, NMDA receptors have been perhaps the most actively investigated for their role in chronic neurodegeneration such as Alzheimer's, Parkinson's, and Huntington's diseases. Recent studies have shown that the NTD of subunit NR2B modulates ion channel gating through the binding of allosteric modulators such as the prototypical compound ifenprodil. In the present paper, the construction of a three-dimensional model for the NR2B modulatory domain is described and docking calculations allow, for the first time, definition of the ifenprodil binding pose at an atomic level and fully explain all the available structure-activity relationships. Moreover, in an attempt to add further insight into the ifenprodil mechanism of action, as it is not completely clear if it binds and stabilizes an open or a closed conformation of the NR2B modulatory domain, a matter, which is fundamental for the rational design of NMDA antagonists, MD simulations followed by an MM-PBSA analysis were performed. These calculations reveal that the closed conformation of the R1-R2 domain, rather than the open, constitutes the high affinity binding site for ifenprodil and that a profound stabilization of the closed conformation upon ifenprodil binding occurs. Thus, for a rational design and/or for virtual screening experiments, the closed conformation of the R1-R2 domain should be taken into account and our 3D model can provide valuable hints for the design of NR2B-selective antagonists.
authors.affiliation: Dipartimento di Chimica Farmaceutica e Tossicologica, Università di Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy. lmarinel@unina.it
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Sandro
authors.initials: S
authors.lastname: Cosconati
authors.forename: Thomas
authors.initials: T
authors.lastname: Steinbrecher
authors.forename: Vittorio
authors.initials: V
authors.lastname: Limongelli
authors.forename: Alessia
authors.initials: A
authors.lastname: Bertamino
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: David A
authors.initials: DA
authors.lastname: Case
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010880:Piperidines / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D018691:Excitatory Amino Acid Antagonists; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C010739:ifenprodil