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Probing the Histamine H1 Receptor Binding Site to Explore Ligand Binding Kinetics
Sebastiaan Kuhne1, Reggie Bosma1, Albert J Kooistra1
1Amsterdam Institute of Molecular and Life Sciences (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
Journal of Medicinal Chemistry
|December 26, 2024
Summary
Structure-kinetic relationship analysis reveals strategies to increase ligand residence time (RT) at the histamine H1 receptor (H1R). Introducing a carboxylic acid group enhanced RT but decreased ligand efficiency, highlighting varied approaches for receptor modulation.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Structural Biology
Background:
- Understanding receptor-ligand interactions is crucial for drug discovery.
- Histamine H1 receptor (H1R) is a key target for allergic conditions.
- Long residence time (RT) ligands can offer improved therapeutic profiles.
Purpose of the Study:
- To investigate structure-kinetic relationships (SKR) for histamine H1 receptor (H1R) ligands.
- To explore fragment growing approaches to mimic known H1R ligands.
- To analyze the impact of structural modifications on ligand binding kinetics.
Main Methods:
- Utilized fragment growing techniques starting with fragment 1 (4-(2-benzylphenoxy)-1-methylpiperidine).
- Designed and synthesized novel ligands to mimic olopatadine, acrivastine, and levocetirizine binding.
- Performed kinetic analyses to determine residence time (RT), ligand efficiency (LE), and kinetic efficiency (KE).
Main Results:
- Introduction of a carboxylic acid moiety increased H1R RT up to 11-fold.
- Negative charge introduction decreased ligand efficiency (LE) but increased kinetic efficiency (KE) up to 8.5-fold.
- Mimics of olopatadine/acrivastine showed greater RT variability (15-fold) compared to levocetirizine mimics (3-fold), indicating differential sensitivity to structural changes.
Conclusions:
- Multiple strategies exist to enhance ligand RT at H1R.
- Different structural modifications yield distinct SKR profiles.
- Levocetirizine mimics demonstrate lower sensitivity to structural variations, suggesting a more robust binding mode.
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