Original article Molecular orbital differentiation of agonist and antagonist activity in the Glycine B -iGluR-NMDA receptor J. Yosa a , M. Blanco b , O. Acevedo c, * , L.R. Lareo d a Universidad Distrital Francisco Jose´ de Caldas, School of Environmental Science, Environmental Engineering, Av. Circunvalar Venado de Oro., Bogota ´, Colombia b Material and Process Simulation Center, Beckman Institute, California Institute of Technology, 1200 E. California Blvd., Pasadena, CA, USA c Pontificia Universidad Javeriana, School of Sciences, Department of Physics, Computational and Structural Biochemistry and Bioinformatics, Carrera 7 a # 43-82, Carlos Ortiz Bldg, S.J., Rm. 108, Bogota ´, Colombia d Pontificia Universidad Javeriana, School of Sciences, Department of Nutrition and Biochemistry, Computational and Structural Biochemistry and Bioinformatics, Carrera 7 a # 43-82, Carlos Ortiz Bldg, S.J., Rm. 108, Bogota ´, Colombia article info Article history: Received 19 November 2008 Received in revised form 29 December 2008 Accepted 9 January 2009 Available online 22 January 2009 Keywords: HOMO LUMO Agonists Antagonist Glycine B -iGluR-NMDA Activity abstract We present various molecular electronic descriptors of agonists and antagonists for Glycine B -iGluR- NMDA receptor with a view to identify computational measures that help differentiate between these two classes of biologically active compounds. We use as reference the glycine site in the NR1 subunit of the NMDA receptor (Glycine B -iGluR-NMDA). Glycine B -iGluR-NMDA receptor is important in learning and memory, and it is involved in various neurodegenerative diseases such as Alzheimer, Parkinson, and Huntington as well as in neuropathies such as schizophrenia and depression. We carried out quantum calculations at two levels, (1) B3LYP Density Functional (6-311G**), and (2) PM3 Hamiltonian for 168 molecules, of which 22 are agonists and 146 are antagonists. Regardless of the quantum mechanical level used we found a consistent signature of agonists versus antagonist action, the energy of the lowest unoccupied molecular orbital (LUMO). Effective differentiation of agonists and antagonists by a single molecular descriptor is seldom seen. We present a plausible electronic structure argument to rationalize these results. Ó 2009 Elsevier Masson SAS. All rights reserved. 1. Introduction The members of the Glutamate family of receptors predomi- nantly mediate excitatory neurotransmission in the mammal brain. These receptors comprise two families: (i) metabotropic receptors (mGluRs), not associated with ion channels, and (ii) ionotropic receptors (iGluRs), associated with cation channels. The latter have two sub-families, non-NMDA type, which are activated by AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazole propionate) and Kainate ((2S,3S,4S)-3-(carboxymethyl)-4-prop-1-en-2-ylpyrroli- dine-2-carboxylate), and the receptors activated by NMDA (N- methyl-D-aspartate). iGluR-NMDA is of great pharmacologic interest because it is implicated in various neurodegenerative disorders, among others: Alzheimer’s [1], Huntington [2], and Parkinson’s diseases [3]. It is also implicated in neuropsychiatry illnesses such as schizophrenia [4] and depression [5], as well as in disorders provoked by alcohol [6] and psychotropic drugs [7]. iGluR-NMDA also takes part in pain sensation [8]. It is also one of the most important receptors for synaptic plasticity, essential for the formation of memories [9]. iGluR-NMDA is activated by glutamate, its natural agonist, but it requires the presence of glycine as co-agonist [10,11] and of modulators such as polyamines, Zn 2þ , and the redox potential of the surrounding medium. When iGluR-NMDA is activated, the ion channels open and become highly permeable to calcium [12], but regulated by voltage and blocked by magnesium (Mg 2þ ) ions [13,14]. Additionally, this channel is a sodium (Na þ ) symporter and potassium (K þ ) antiporter. iGluR-NMDA is a complex containing from 3 to 5 subunits [15], and in most configurations include at least one copy of NR1 subunit in addition to NR2 (A–D) [16] or NR3 (A–B) [17]. Subunit NR1 appears to be the key for the formation of the channel. NR1 contains the glycine or glycine B -binding site, insensible to strych- nine. NR2 contains the glutamate-binding site. iGluR-NMDA contains several modulating sites that allow an ample number of allosteric interactions [18–21], polyamine sites, a Zn 2þ site, a phosphorylation site, and a site modulated by different states of pH and redox potential. Various substances such * Corresponding author. Tel./fax: þ57 1 3208320x4136. E-mail address: oacevedo@javeriana.edu.co (O. Acevedo). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2009.01.013 European Journal of Medicinal Chemistry 44 (2009) 2960–2966