Dataset Information

Differential Regulation of Bilastine Affinity for Human Histamine H₁ Receptors by Lys 179 and Lys 191 via Its Binding Enthalpy and Entropy.

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 Lys179^ECL2 and Lys191^5.39 of human H₁ receptors might contribute to increased affinity of these antihistamines to H₁ receptors. In this study, we evaluated the roles of Lys179^ECL2 and Lys191^5.39 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 Lys179^ECL2 or Lys191^5.39 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 Lys179^ECL2 and Lys191^5.39 to alanine reduced the affinity of bilastine to H₁ receptors by reducing enthalpy- and entropy-dependent binding forces, respectively. These results suggest that Lys179^ECL2 and Lys191^5.39 differentially contribute to the increased binding affinity to bilastine via electrostatic and hydrophobic binding forces.

SUBMITTER: Akimoto H

PROVIDER: S-EPMC7915449 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

Differential Regulation of Bilastine Affinity for Human Histamine H1 Receptors by Lys 179 and Lys 191 via Its Binding Enthalpy and Entropy.

Akimoto Hayato H Sugihara Minoru M Hishinuma Shigeru S

International journal of molecular sciences 20210206 4

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 H<sub ...[more]

PMID: 33562121

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Project description:BACKGROUND:Chronic spontaneous urticaria (CSU) is characterized by the spontaneous appearance of wheals, angioedema, or both for > 6 weeks. Continuous treatment with H1-antihistamines is used as a first-line treatment for CSU. However, H1-antihistamine treatment leads to absence of symptoms in less than 50% of patients with CSU. Although Japanese guidelines for the diagnosis and treatment of urticaria recommend an increase in the H1-antihistamine dose or a switch to other H1-antihistamines, there is no evidence supporting a switch to other H1-antihistamines in patients with refractory CSU who are unresponsive to H1-antihistamines at the licensed dose. METHODS:We will conduct a multicenter, open-label, non-inferiority, randomized, parallel, comparison study to determine if the efficacy of bilastine 20 mg is not inferior to that of a twofold H1-antihistamine dose increase in patients with refractory CSU who are unresponsive to H1-antihistamines at the licensed dose. This study will be performed at 15 academic hospitals in Japan, and the administration period (increasing the H1-antihistamine dose twofold vs. switching to bilastine 20 mg) will be 7 days. Participants (n = 150) will be randomized to either an increased H1-antihistamine dose or a switch to bilastine 20 mg at a 1:1 ratio. The primary endpoint, mean of the total symptom score of 5-7 days after the intervention, will be evaluated. The secondary objective is to determine if the safety of bilastine 20 mg regarding somnolence is superior to that of a twofold dose increase of H1-antihistamines. This will be measured by a change in the Japanese version of the Epworth Sleepiness Scale from baseline to 7 days after starting the intervention. DISCUSSION:This multicenter, open-label, non-inferiority, randomized, parallel, comparison study will be, to our knowledge, the first well-designed clinical study to evaluate the efficacy of a switch to other H1-antihistamines in patients with refractory CSU who are unresponsive to H1-antihistamines at the licensed doses. This trial will provide evidence of the efficacy and safety of bilastine when treatment is switched in patients with refractory CSU who are unresponsive to H1-antihistamines at the licensed dose. TRIAL REGISTRATION:Japan Registry of Clinical Trials (jRCT), jRCTs051180105. Registered on 8 March 2019.

Project description:Exploring the protein-folding problem has been a longstanding challenge in molecular biology and biophysics. Intramolecular hydrogen (H)-bonds play an extremely important role in stabilizing protein structures. To form these intramolecular H-bonds, nascent unfolded polypeptide chains need to escape from hydrogen bonding with surrounding polar water molecules under the solution conditions that require entropy-enthalpy compensations, according to the Gibbs free energy equation and the change in enthalpy. Here, by analyzing the spatial layout of the side-chains of amino acid residues in experimentally determined protein structures, we reveal a protein-folding mechanism based on the entropy-enthalpy compensations that initially driven by laterally hydrophobic collapse among the side-chains of adjacent residues in the sequences of unfolded protein chains. This hydrophobic collapse promotes the formation of the H-bonds within the polypeptide backbone structures through the entropy-enthalpy compensation mechanism, enabling secondary structures and tertiary structures to fold reproducibly following explicit physical folding codes and forces. The temperature dependence of protein folding is thus attributed to the environment dependence of the conformational Gibbs free energy equation. The folding codes and forces in the amino acid sequence that dictate the formation of β-strands and α-helices can be deciphered with great accuracy through evaluation of the hydrophobic interactions among neighboring side-chains of an unfolded polypeptide from a β-strand-like thermodynamic metastable state. The folding of protein quaternary structures is found to be guided by the entropy-enthalpy compensations in between the docking sites of protein subunits according to the Gibbs free energy equation that is verified by bioinformatics analyses of a dozen structures of dimers. Protein folding is therefore guided by multistage entropy-enthalpy compensations of the system of polypeptide chains and water molecules under the solution conditions.

Dataset Information

Differential Regulation of Bilastine Affinity for Human Histamine H₁ Receptors by Lys 179 and Lys 191 via Its Binding Enthalpy and Entropy.

Publications

Differential Regulation of Bilastine Affinity for Human Histamine H<sub>1</sub> Receptors by Lys 179 and Lys 191 via Its Binding Enthalpy and Entropy.

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