Probing the Histamine H1 Receptor Binding Site to Explore Ligand Binding Kinetics

Sebastiaan Kuhne, Reggie Bosma, Albert J. Kooistra, Rick Riemens, Marc C.M. Stroet, Henry F. Vischer, Chris de Graaf, Maikel Wijtmans, Rob Leurs, Iwan J.P. de Esch*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Analysis of structure-kinetic relationships (SKR) can contribute to an improved understanding of receptor-ligand interactions. Here, fragment 1 (4-(2-benzylphenoxy)-1-methylpiperidine) was used in different fragment growing approaches to mimic the putative binding mode of the long residence time (RT) ligands olopatadine, acrivastine, and levocetirizine at the histamine H1 receptor (H1R). SKR analyses reveal that introduction of a carboxylic acid moiety can increase RT at H1R up to 11-fold. Ligand efficiency (LE) decreases upon the introduction of the negatively charged group, whereas kinetic efficiency (KE) increases up to 8.5-fold. The olopatadine/acrivastine mimics give up to 15-fold differences in the RT, while the levocetirizine mimics afford similar RTs with only a 3-fold difference. Therefore, the levocetirizine mimics are less sensitive to structural changes. This study illustrates that for H1R, there are several ways to increase RT but the different strategies differ significantly in SKR.

Original languageEnglish
Pages (from-to)448-464
Number of pages17
JournalJournal of medicinal chemistry
Volume68
Issue number1
Early online date26 Dec 2024
DOIs
Publication statusPublished - 9 Jan 2025

Bibliographical note

Publisher Copyright:
© 2024 The Authors. Published by American Chemical Society.

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