3D-QSAR CoMFA Study to Predict Orientation of Suprahistaprodifens and Phenoprodifens in the Binding-Pocket of Four Histamine H1 -Receptor Species.

Abstract

Several phenylhistamines and histaprodifens were identified to act as (partial) agonists at the histamine H1 -receptor (H1 R). The large diversity of these compounds led to pKi values in a range between 4.5-7.5 at human, rat, bovine and guinea-pig histamine H1 R. Hybrid molecules, consisting of two different H1 R-agonist partial structures, like suprahistaprodifens or phenoprodifens for example, or compounds with a dimeric histamine moiety are able to bind in two different orientations into the binding-pocket of the H1 R. In order to predict the percentage of ligand bound in orientation 1 or in orientation 2, 3D-QSAR studies at four H1 R species were performed. The training set contains ligands which can only bind in one orientation and the test set all ligands with two possible orientations. In general, the predicted pKi values of the test compounds were in good correlation to the experimental ones. Additionally, the predicted pKi values for all ligands with two possible orientations were used to calculate the percentage of the hybrid ligands bound in orientation 1 and 2. Our models suggest that the preferred orientation of these hybrid molecules is dependent on ligand and H1 R species.