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Molecular Determinants of the Kinetic Binding Properties of Antihistamines at the Histamine H1 Receptors

1
Department of Pharmacodynamics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
2
Department of Medical Molecular Informatics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
*
Author to whom correspondence should be addressed.
Academic Editor: Massimo Triggiani
Int. J. Mol. Sci. 2021, 22(5), 2400; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052400
Received: 30 January 2021 / Revised: 17 February 2021 / Accepted: 25 February 2021 / Published: 27 February 2021
(This article belongs to the Special Issue Molecular Biology of Histamine Systems)
The binding affinity of ligands for their receptors is determined by their kinetic and thermodynamic binding properties. Kinetic analyses of the rate constants of association and dissociation (kon and koff, respectively) of antihistamines have suggested that second-generation antihistamines have a long duration of action owing to the long residence time (1/koff) at the H1 receptors. In this study, we examined the relationship between the kinetic and thermodynamic binding properties of antihistamines, followed by an evaluation of the structural determinants responsible for their kinetic binding properties using quantitative structure–activity relationship (QSAR) analyses. We found that whereas the binding enthalpy and entropy might contribute to the increase and decrease, respectively, in the koff values, there was no significant relationship with the kon values. QSAR analyses indicated that kon and koff values could be determined by the descriptors FASA_H (water-accessible surface area of all hydrophobic atoms divided by total water-accessible surface area) and vsurf_CW2 (a 3D molecular field descriptor weighted by capacity factor 2, the ratio of the hydrophilic surface to the total molecular surface), respectively. These findings provide further insight into the mechanisms by which the kinetic binding properties of antihistamines are regulated by their thermodynamic binding forces and physicochemical properties. View Full-Text
Keywords: antihistamine; affinity; association rate constant; dissociation rate constant; enthalpy; entropy; H1 receptor antihistamine; affinity; association rate constant; dissociation rate constant; enthalpy; entropy; H1 receptor
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MDPI and ACS Style

Akimoto, H.; Uesawa, Y.; Hishinuma, S. Molecular Determinants of the Kinetic Binding Properties of Antihistamines at the Histamine H1 Receptors. Int. J. Mol. Sci. 2021, 22, 2400. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052400

AMA Style

Akimoto H, Uesawa Y, Hishinuma S. Molecular Determinants of the Kinetic Binding Properties of Antihistamines at the Histamine H1 Receptors. International Journal of Molecular Sciences. 2021; 22(5):2400. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052400

Chicago/Turabian Style

Akimoto, Hayato, Yoshihiro Uesawa, and Shigeru Hishinuma. 2021. "Molecular Determinants of the Kinetic Binding Properties of Antihistamines at the Histamine H1 Receptors" International Journal of Molecular Sciences 22, no. 5: 2400. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052400

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