Virtual Screening And Molecular Design Of Computer Aided μ - Opioid Receptor Agonists

Opioid receptors belong to the superfamily of G-protein coupled receptors(GPCRs) and have 7 transmembrane spanning proteins. There are three well-adopted subtypes of opioid receptors:δopioid,μopioid andκopioid . Theμopioid receptor is the primary site of action in the brain for opioid neuropeptides as well as opiate drugs. However, the three-dimensional structures of bioreceptors remain unclear, since no X-ray data ofμopioid receptor are available. So we can bulid a 3D model ofμopioid receptor by homelogy modeling. The properties of several sequ- ences were analyzed by comparing with humanμopioid receptor, and a great similarity was found between bovind rhodopsin(PDB code:1F88)and humanμoipiod receptor. Therefore bovine rhodopsin was selected as template. Homologous 3D model of humanμopioid receptor was built on the basis of the crystal coordinates of bovine rhodopsin, secondary structure ofμopioid receptor was also predicted, while the reliability of the model was assessed by Ramach- andran plot and ProTab analysis. The active site of humanμopioid receptor was searched by Biopolymer/SiteID analysis and important functional residues were located at the active site, furthermore, new important functional residues were also predicted. The results agree well to the experimental results reported. The research provided a basis for the rational design of specific agonist and antagonist to the target receptor and the discovery of novel and more potent drugs.Fentanyl derivates asμopioid receptor agonist, a powerful analgesic effect can be used to alleviate acute and chronic pain, but there are obvious respiratory depression, constipation, urinary retention, and the potential to produce chemical dependency. The 3D structures of these compounds were sketched and optimized with molecular modeling software package Sybyl. A pharmacophore model was constructed by GALAHAD modules. The model consists of two benzene rings hydrophobic centre, a piperidine ring hydrophobic centre, a donor atom nitrogen and four acceptor atoms oxygen. The model has good predictive ability, providing hints for the future design of new derivatives with higher potency and specificity and exploring the binding mode and mechanism of fentanyl derivatives with u opioid receptorA predictive 3D-QSAR model that correlates the biological activities with the chemical structures of a series of 4-phenylpiperidine derivatives asμopioid agonists was developed by means of comparative molecular field analysis (CoMFA). The stabilities of the 3D-QSAR models were verified by the leave-one-out cross-validation method. Best predictions were obtained with CoMFA standard model(q2=0.504, N=6, r2=0.968). Moreover, the predictive capabilities of the models were validated by an external test set and possessing promising predictive ability.The model revealed that how steric and electrostatic interactions contribute to agonists bioactivities. The models could provide structural modification information for more potentμopioid agonists.In order to elucidate the interaction mechanism of 4-phenylpiperidine derivatives withμopioid receptor and design newμopioid agonist, molecular docking based on Surflex-docking also performed to explore the binding mode of 4-phenylpiperidine derivatives with u opioid receptor and provide hints for the future design of new derivatives with higher potency and specificity. A possible mechanism ofμopioid receptor activation is discussed.The first database of fentanyl derivatives with anti-terrorism activity was developed using VC + + and Access2007 in China. The building process and retrieval methods for the database were introduced. The data in the database and the meaning of building the database of fentanyl derivatives with anti-terrorism activity were described. The database has a function of quick adding, search and export of related information and lays the foundation for compounds having anti-terrorism activity related research work.The research is on the basis of the ligand and receptor. A homologous 3D model of humanμopioid receptor was built on the basis of the crystal coordinates of bovine rhodopsin, a predictive 3D-QSAR model also was constructed. A pharmacophore model was obtained by GALAHAD modules. In order to elucidate the interaction mechanism of fentanyl derivatives withμopioid receptor, several Ligands are docked into the protein, 30 new compounds was designed . The first database of fentanyl derivatives with anti-terrorism activity was developed using VC + + and Access2007. The research provided a basis for the rational design of specific agonist and antagonist to the target receptor and the discovery of novel and more potent drugs, can aided futher sythesis.