Insights into subtype selectivity of opioid agonists by ligand-based and structure-based methods.
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.
Cheng
Jianxin
J
Laboratory of Molecular Modeling & Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China.
Liu
Guixia
G
Zhang
Jing
J
Xu
Zhejun
Z
Tang
Yun
Y
D000701:Analgesics, Opioid / Q000819:agonists*; D001665:Binding Sites; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011957:Receptors, Opioid / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000701:Analgesics, Opioid; D008024:Ligands; D011957:Receptors, Opioid