Development of a pharmacophore model for histamine H3 receptor antagonists, using the newly developed molecular modeling program SLATE

Article abstract of DOI:10.1021/jm001109k

New molecular modeling tools were developed to construct a qualitative pharmacophore model for histamine H₃ receptor antagonists. The program SLATE superposes ligands assuming optimum hydrogen bond geometry. One or two ligands are allowed to flex in the procedure, thereby enabling the determination of the bioactive conformation of flexible H₃ antagonists. In the derived model, four hydrogen-bonding site points and two hydrophobic pockets available for binding antagonists are revealed. The model results in a better understanding of the structure-activity relationships of H₃ antagonists. To validate the model, a series of new antagonists was synthesized. The compounds were designed to interact with all four hydrogen-bonding site points and the two hydrophobic pockets simultaneously. These ligands have high H₃ receptor affinity, thereby illustrating how the model can be used in the design of new classes of H₃ antagonists.