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The binding orientations of structurally-related ligands can differ; A cautionary note.
Marc-David Ruepp1, Hao Wei2, Michele Leuenberger1
1Department of Chemistry and Biochemistry, University of Bern, Bern, Switzerland.
Neuropharmacology
|February 1, 2017
Summary
Tropisetron and granisetron binding orientations differ in 5-HT3 receptors, challenging homologous protein crystal structure predictions. This highlights the need for caution when using structural homologues for drug development.
Area of Science:
- Structural biology
- Pharmacology
- Computational chemistry
Background:
- Crystal structures of homologous proteins are used to study ligand-receptor interactions, but may not accurately reflect binding in the target receptor.
- Tropisetron binds to both 5-HT3 and alpha7 nicotinic acetylcholine receptors (nAChR), with differing affinities, while granisetron only binds to 5-HT3 receptors.
Purpose of the Study:
- To investigate the binding orientation of tropisetron and granisetron in the 5-HT3 receptor.
- To assess the reliability of homologous protein crystal structures (AChBP) for predicting ligand binding in 5-HT3 receptors.
Main Methods:
- In silico modeling and docking of tropisetron and granisetron.
- Radioligand binding assays using cysteine-substituted 5-HT3 receptor mutants.
- Structure-activity relationship studies on synthesized ligand derivatives.
Main Results:
- Differential effects of cysteine substitutions on tropisetron and granisetron binding suggest distinct orientations.
- Structure-activity relationships further supported different binding poses for the two ligands.
- Contrary to crystal structures of the homologue AChBP, tropisetron and granisetron adopt different orientations in the 5-HT3 receptor.
Conclusions:
- Structurally similar ligands can adopt different binding orientations within the same receptor site.
- Caution is advised when extrapolating ligand binding information from homologous protein crystal structures to target receptors.
- Findings have implications for structure-based drug design and therapeutic development.
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