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 language | English |
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Pages (from-to) | 448-464 |
Number of pages | 17 |
Journal | Journal of medicinal chemistry |
Volume | 68 |
Issue number | 1 |
Early online date | 26 Dec 2024 |
DOIs | |
Publication status | Published - 9 Jan 2025 |
Bibliographical note
Publisher Copyright:© 2024 The Authors. Published by American Chemical Society.