Rational Drug Design Using Mammalian Cell Lines Expressing Site-Directed Mutants of the Human H₁ Histaminic Receptor

Abstract

The binding cavity of histamine and histamine antagonists has been explored using site-directed mutagenesis of the human histamine H₁ receptor and the amino acids involved in ligand binding have been identified. Whereas Asp₁₀₇ and Phe₁₉₉ appeared important for both agonists and antagonists, two additional amino acids (Asn₁₉₈ and Trp₁₀₃) were required for efficient histamine binding. The binding site of antagonists was best defined as resulting from a strong ionic bond to Asp₁₀₇, an orthogonal interaction between one of the aromatic rings with Phe₁₉₉, and probably a hydrophobic interaction between the second aromatic ring and the lipophilic amino acids of the upper part of TMIV and TMV. This is consistent with structure-activity data of most described antagonists.