Insights into subtype selectivity of opioid agonists by ligand-based and structure-based methods.

Autor: Jianxin Cheng, Guixia Liu, Jing Zhang, Zhejun Xu, Yun Tang
Předmět:
Zdroj: Journal of Molecular Modeling; Mar2011, Vol. 17 Issue 3, p477-493, 17p, 5 Diagrams, 1 Chart, 1 Graph
Abstrakt: To probe the selective mechanism of agonists binding to three opioid receptor subtypes, ligand-based and receptor-based methods were implemented together and subtype characteristics of opioid agonists were clearly described. Three pharmacophore models of opioid agonists were generated by the Catalyst/HypoGen program. The best pharmacophore models for μ, δ and κ agonists contained four, five and five features, respectively. Meanwhile, the three-dimensional structures of three receptor subtypes were modeled on the basis of the crystal structure of β2-adrenergic receptor, and molecular docking was conducted further. According to these pharmacophore models and docking results, the similarities and differences among agonists of three subtypes were identified. μ or δ agonists, for example, could form one hydrogen bond separately with Tyr129 and Tyr150 at TMIII, whereas κ ones formed a π-π interaction in that place. These findings may be crucial for the development of novel selective analgesic drugs. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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