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WIN55212-2 docking to the CB1 cannabinoid receptor and multiple pathways for conformational induction
Joong-Youn Shim1, Allyn C Howlett
1Neuroscience of Drug Abuse Research Program, J. L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina 27707, USA. jyshim@nccu.edu
Journal of Chemical Information and Modeling
|May 23, 2006
Summary
Key pharmacophoric elements of (aminoalkyl)indole (AAI) cannabinoid receptor agonists were explored. Aromatic-aromatic interactions of the naphthyl ring are crucial for both binding and inducing conformational changes in the CB1 receptor.
Area of Science:
- Medicinal Chemistry
- Molecular Pharmacology
- Computational Chemistry
Background:
- The (aminoalkyl)indole (AAI) scaffold contains key pharmacophoric elements: an aminoalkyl moiety, a lipophilic aroyl group, and a heterocyclic indole ring.
- Cannabinoid receptor 1 (CB1) agonists are crucial targets for various therapeutic applications.
Purpose of the Study:
- To elucidate the binding interactions of AAIs within the CB1 receptor.
- To investigate the role of ligand structure in inducing CB1 receptor conformational changes.
Main Methods:
- Utilized a docking approach combining Monte Carlo (MC) and molecular dynamics (MD) simulations.
- Explored the docking space of (R)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthalenyl)methanone (WIN55212-2; 1) within the CB1 receptor.
- Correlated extensive structure-activity relationship (SAR) data with calculated binding energies.
Main Results:
- Proposed two alternative binding conformations (aroyl-up1 and aroyl-up2) based on ligand orientation within the CB1 receptor.
- Demonstrated that the aroyl ring moiety of WIN55212-2 acts as a steric trigger for inducing CB1 receptor conformational changes.
- Highlighted the importance of aromatic-aromatic interactions for both ligand binding and receptor conformational modulation.
Conclusions:
- Aromatic-aromatic interactions are critical for the binding of AAIs to the CB1 receptor.
- The ligand's aroyl group plays a significant role in inducing receptor conformational changes.
- Ligand-specific binding interactions can lead to distinct conformational alterations in the CB1 receptor.
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