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.
J. Med. Chem., 2003, 46 (19), pp 4063–4069 DOI: 10.1021/jm030833a