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