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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
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A binding kinetics study of human adenosine A3 receptor agonists
Lizi Xia1, Athina Kyrizaki1, Dilip K Tosh2
1Division of Medicinal Chemistry, LACDR, Leiden University, The Netherlands.
Biochemical Pharmacology
|January 7, 2018
Summary
This study introduces binding kinetics analysis for human adenosine A3 receptor agonists, revealing structure-kinetics relationships crucial for developing new anti-inflammatory and anticancer drugs.
Area of Science:
- Pharmacology
- Medicinal Chemistry
- Drug Discovery
Background:
- The human adenosine A3 receptor (hA3R) is a potential drug target for inflammatory diseases and cancer.
- Selective hA3R agonists are in clinical trials for their anti-inflammatory and anticancer effects.
- Drug-target binding kinetics is an emerging parameter for compound selection in early drug discovery.
Purpose of the Study:
- To validate a competition association assay for determining hA3R agonist kinetics.
- To investigate structure-kinetics relationships (SKR) of hA3R agonists.
- To explore the utility of binding kinetics beyond affinity in hA3R agonist development.
Main Methods:
- Validated a competition association assay for hA3R agonist kinetics.
- Determined affinities and Kinetic Rate Index (KRI) for nucleoside analogues using radioligand binding assays.
- Performed full kinetics characterization for selected analogues.
Main Results:
- Identified SKR, associating longer residence times with methanocarba and specific adenine substitutions.
- Classified agonists into three subgroups based on a k(on)-k(off)-K(D) kinetic map.
- Observed a residence time 'cliff' potentially linked to C2-arylalkynyl substitutions in methanocarba derivatives.
Conclusions:
- Binding kinetics analysis provides valuable insights for hA3R agonist development.
- Kinetic parameters, in addition to affinity, aid in selecting promising drug candidates.
- Findings support the use of kinetics-driven approaches in early-stage drug discovery for hA3R.
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