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Alpha2-adrenergic receptor (α2-AR) subtypes, acting mainly on the central nervous and cardiovascular systems, represent important targets for drug design, confirmed by the high number of studies published so far. Presently, only few α2-AR subtype selective compounds are known. Using homology modeling and ligand docking, the present study analyzes the similarities and differences between binding sites, and between extracellular loops of the three subtypes of α2-AR. Several α2-AR subtype selective ligands were docked in the active sites of the three α2-AR subtypes, key interactions between ligands and receptors were mapped, and the predicted results were compared to experimental results. Binding site analysis reveals a strong identity between important amino acid residues in each receptor, the very few differences being the key towards modulating selectivity of α2-AR ligands. The observed differences between binding site residues provide an excellent starting point for virtual screening of chemical databases in order to identify potentially selective ligands for α2-ARs.

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BackgroundResearch interest in phosphonates metal organic frameworks (MOF) has increased extremely in the last two decades, because of theirs fascinating and complex topology and structural flexibility. In this paper we present a mathematical model for ligand/metal ion ratio of an octahedral (Oh) network of cobalt vinylphosphonate (Co(vP)·H2O).ResultsA recurrent relationship of the ratio between the number of ligands and the number of metal ions in a lamellar octahedral (Oh) network Co(vP)·H2O, has been deducted by building the 3D network step by step using HyperChem 7.52 package. The mathematical relationship has been validated using X ray analysis, experimental thermogravimetric and elemental analysis data.ConclusionsBased on deducted recurrence relationship, we can conclude prior to perform X ray analysis, that in the case of a thermogravimetric analysis pointing a ratio between the number of metal ions and ligands number around 1, the 3D network will have a central metal ion that corresponds to a single ligand. This relation is valid for every type of supramolecular network with divalent metal central ion Oh coordinated and bring valuable information with low effort and cost.

ABSTRACT:The human muscarinic M3 receptor (hM3) and its interactions with selective agonists and antagonists were investigated by means of combined homology and docking approach. Also, two pharmacophoric models for the hM3 agonist and antagonist binding sites were proposed. The three-dimensional (3D) structure of hM3 receptor was modeled based on the high-resolution X-ray structure of bovine rhodopsin from the Protein Data Bank (PDB). To validate the reliability of the model obtained, the main chain torsion angles phi (⌿ ) and psi (⌽) were examined in a Ramachandran plot, and all omega angles were measured for peptidic bond planarity. The characteristics of the active site, the position, and the orientation of ligands in situ, as well as the binding modes of the representative agonists and antagonists, were analyzed by applying a molecular docking technique using the AutoDock 3.0.5 program. Specific interactions responsible for recognition of the hM3 receptor, like ionic bond formed between protonated amine of the ligands and the Asp3.6 side chain were identified. Structure-reactivity relationships have been explained by analyzing the 3D structure of the hM3 model and the ligand conformations resulted from molecular docking simulation.