Abstract
Bilastine, a zwitterionic second-generation antihistamine containing a carboxyl group, has higher selectivity for H1 receptors than first-generation antihistamines. Ligand-receptor docking simulations have suggested that the electrostatic interaction between the carboxyl group of second-generation antihistamines and the amino group of Lys179ECL2 and Lys1915.39 of human H1 receptors might contribute to increased affinity of these antihistamines to H1 receptors. In this study, we evaluated the roles of Lys179ECL2 and Lys1915.39 in regulating the electrostatic and hydrophobic binding of bilastine to H1 receptors by thermodynamic analyses. The binding enthalpy and entropy of bilastine were estimated from the van ’t Hoff equation using the dissociation constants. These constants were obtained from the displacement curves against the binding of [3H] mepyramine to membrane preparations of Chinese hamster ovary cells expressing wild-type human H1 receptors and their Lys179ECL2 or Lys1915.39 mutants to alanine at various temperatures. We found that the binding of bilastine to wild-type H1 receptors occurred by enthalpy-dependent binding forces and, more dominantly, entropy-dependent binding forces. The mutation of Lys179ECL2 and Lys1915.39 to alanine reduced the affinity of bilastine to H1 receptors by reducing enthalpy- and entropy-dependent binding forces, respectively. These results suggest that Lys179ECL2 and Lys1915.39 differentially contribute to the increased binding affinity to bilastine via electrostatic and hydrophobic binding forces.
Highlights
Published: 6 February 2021It is known that Gq/11 -protein-coupled H1 receptors are involved in mediating allergic and inflammatory responses in peripheral tissues and the state of arousal in the central nervous system [1,2,3,4,5,6,7,8]
Some second-generation antihistamines have zwitterionic properties owing to the presence of carboxyl groups, which help reduce their side effects such as sedation and impaired performance resulting from the blockade of H1 receptors in the central nervous system via their penetration into the brain through the blood–brain barrier
Ligand-receptor docking simulations based on the crystal structure of human H1 receptor indicated that the carboxyl group of second-generation antihistamines, Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations
Summary
It is known that Gq/11 -protein-coupled H1 receptors are involved in mediating allergic and inflammatory responses in peripheral tissues and the state of arousal in the central nervous system [1,2,3,4,5,6,7,8]. Such as olopatadine, levocetirizine, fexofenadine, and acrivastine, appeared to form a salt bridge with Lys179ECL2 and/or Lys1915.39. This bridge might have contributed to the increased selectivity of carboxylated second-generation antihistamines for H1 receptors [21]. Ligand-receptor docking simulations based on the crystal structure of human H1 receptor indicated that the carboxyl group of second-generation antihistaO mines, such as olopatadine, levocetirizine, fexofenadine, and acrivastine, appeared to form a salt bridge with Lys179ECL2 and/or Lys1915.39.
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