Selectivity fields: comparative molecular field analysis (CoMFA) of the glycine/NMDA and AMPA receptors.

An approach for evaluation of binding selectivity was suggested and exemplified using glycine/NMDA and AMPA receptors. For analyzing the pairwise selectivity, we propose to use the difference between biological activities (expressed as -log Ki) of ligands with respect to different receptor subtypes as a dependent variable for building comparative molecular field analysis (CoMFA) models. The resulting fields (which will be referred to as the "selectivity fields") indicate the ways of increasing selectivity of binding, inhibition, etc. As an example, CoMFA of a set of pyrazolo[1,5-c]quinazolines and triazolo[1,5-c]quinazolines was used for considering the binding selectivity with respect to glycine/NMDA and AMPA receptors. In addition, the mapping of these fields onto the molecular models of the corresponding receptors makes it possible to reveal the reasons for experimentally observed selectivity as well as to suggest additional ways of increasing selectivity.

[1]  C. Costagli,et al.  Synthesis, ionotropic glutamate receptor binding affinity, and structure-activity relationships of a new set of 4,5-dihydro-8-heteroaryl-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylates analogues of TQX-173. , 2001, Journal of medicinal chemistry.

[2]  Igor I Baskin,et al.  CoMFA and homology-based models of the glycine binding site of N-methyl-d-aspartate receptor. , 2003, Journal of medicinal chemistry.

[3]  David S. Goodsell,et al.  Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function , 1998 .

[4]  C. Costagli,et al.  4,5-Dihydro-1,2,4-triazolo[1,5-a]quinoxalin-4-ones: excitatory amino acid antagonists with combined glycine/NMDA and AMPA receptor affinity. , 1999, Journal of medicinal chemistry.

[5]  P. Dean,et al.  Recent advances in structure-based rational drug design. , 2000, Current opinion in structural biology.

[6]  Todd J. A. Ewing,et al.  DREAM++: Flexible docking program for virtual combinatorial libraries , 1999, J. Comput. Aided Mol. Des..

[7]  R. Cramer,et al.  Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. , 1988, Journal of the American Chemical Society.

[8]  I. Tikhonova,et al.  Structural basis for understanding structure-activity relationships for the glutamate binding site of the NMDA receptor. , 2002, Journal of medicinal chemistry.

[9]  V. Carlá,et al.  Synthesis and biological evaluation of a new set of pyrazolo[1,5-c]quinazoline-2-carboxylates as novel excitatory amino acid antagonists. , 2002, Journal of medicinal chemistry.

[10]  E. Gouaux,et al.  Mechanisms for Activation and Antagonism of an AMPA-Sensitive Glutamate Receptor Crystal Structures of the GluR2 Ligand Binding Core , 2000, Neuron.

[11]  I. Tikhonova,et al.  A Spatial Model of the Glycine Site of the NR1 Subunit of NMDA-Receptor and Ligand Docking , 2004, Doklady Biochemistry and Biophysics.