PHARMACOPHORIC SEARCH AND 3D-QSAR COMPARATIVE MOLECULAR-FIELD ANALYSIS STUDIES ON AGONISTS OF MELATONIN SHEEP RECEPTORS

Conformational analysis was used to characterize the agonist pharmacop hore for melatonin sheep brain receptor recognition and activation. Th e molecular geometry shared by all conformations of the selected activ e ligands was determined. Assuming that all the compounds interact at the same binding site at the receptor level, 2-iodomelatonin pharmacop horic conformation served as a template for the superimposition of 64 structurally heterogeneous agonists constituting the training set used to perform a three-dimensional quantitative structure-activity relati onship study via the comparative molecular field analysis method. A st atistically significant model was obtained for the totality of the com pounds (n = 64, q(2) = 0.62, N = 6, r(2) = 0.96, s = 0.28, F = 249) wi th steric, electrostatic, and lipophilic relative contributions of 28% , 35%, and 37%, respectively. The predictive power of the proposed mod el was discerned by successfully testing the 78 agonist ligands consti tuting the test set. The model so obtained and validated brings import ant structural insights to aid the design of novel melatoninergic agon ist ligands prior to their synthesis.