1,721,053 research outputs found
Homology Modeling of Metabotropic Glutamate Receptors (mGluRs). Structural Motifs Affecting Binding Modes and Pharmacological Profile of mGluR1 Agonists and Competitive Antagonists
No full textA three-dimensional model of the amino terminal domain (ATD) of the mGluR1 receptor subtype was constructed on the basis of the previously reported sequence homology with bacterial periplasmic proteins. The model was utilized for revealing structural motifs affecting the interaction with mGluR1 agonists and competitive antagonists. The agonist binding site region, identified on the basis of published site-directed mutagenesis experiments, is located on the surface of one of the two lobes constituting the mGluR1 ATD. A number of electrostatic and hydrogen-bonding interactions can be detected between mGluR1 agonists such as l-Glu (1), Quis (2), and (1S,3R)-ACPD (4) and binding site residues. A different binding mode was proposed for mGluR1 competitive antagonists such as 4CPG (5), 4C3HPG (6), and UPF523 (10). Interactions with both lobes of the ATD of mGluR1 and the lack of a specific role for the phenyl moiety of mGluR1 antagonists are important features of the proposed antagonist binding mode. The correspondence of the molecular modeling results with the pharmacological data of mGluR1 agonists and competitive antagonists is a confirmation of the plausibility of the model
Conformational requirements for interaction of L-Glutamic acid with metabotropic EEA receptors
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QSAR and Molecular Modeling Studies of Baclofen Analogs as GABAB Agonists. Insights into the Role of the Aromatic Moiety in GABAB Binding and Activation.
No full textn integrated QSAR/molecular modeling study is carried out on a series of baclofen analogues with the aim of addressing the role of their aromatic moiety in GABAB receptor binding and activation. The strong correlation found between electronic descriptors (HOMO and LUMO orbital energies) and the biological activity expressed as receptor binding is discussed also on the basis of available experimental mutagenesis data and of the results obtained from homology modeling of GABAB receptor. In particular, it can be inferred from the QSAR analysis that the ability of being involved in aromatic−aromatic π interaction is the distinctive feature of the p-chlorophenyl moiety of baclofen. This conclusion is confirmed by homology modeling and docking studies which indicate that the p-chlorophenyl moiety of baclofen is disposed into a pocket formed by Tyr366 and Tyr395. These results are discussed in terms of mechanism of GABAB activation promoted by baclofen or GABA
Molecular Dynamic Simulation of the ligand binding domain of mGluR1 in response to agonist and antagonist binding
No full textThe interdomain movements of the ligand binding domain (LBD) of mGluR1 in response to agonist or antagonist binding are studied by 2 ns molecular dynamics (MD) simulations. Our results indicate that MD is able to reproduce many of the experimentally determined features of the open and closed conformations of LBD. Analysis of the ligand behavior over time allows to delineate some of the molecular determinants responsible for the agonist-induced or antagonist-blocked LBD response
The effect of the copper(II) salt anion in the Chiral Ligand-Exchange Chromatography of amino acids
No full textDue to the strong involvement in numerous biochemical processes, the separation and resolution of amino acids is a continuously challenging task. Among the experimental parameters affecting the performances in a Chiral Ligand-Exchange Chromatography (CLEC) environment, the effect of the copper(II) salt counter-ion has received very limited attention. Aimed at evaluating the Cu(II) counter-ion effect upon the overall chromatographic performances when the S-Trityl-(R)-Cysteine is adopted as the chiral selector for the coated stationary phase, a number of both organic (acetate, formate, gluconate, trifluoromethane-sulfonate) and inorganic (bromide, chloride, nitrate, perchlorate, sulfate) salts has been engaged for the enantiomer separation of a selected set of aliphatic (Allo-Ile, Ile, Leu, Nor-Leu, Nor-Val, Val) and aromatic (AIDA, ATIDA, His, Phe, Phg, Tyr) amino acids. By varying the physico-chemical nature of the Cu(II) anion, a pronounced impact upon the resolution factor (RS) has been observed. Even if to a lesser extent, the enantioseparation factor values () underwent variation, as well. A molecular modelling investigation has also been carried out as a rationalization attempt of the observed chromatographic outcomes
The pseudoactive site as a tool for indirect drug design. Application to inhibitors of kynurenine-3-hydroxylase
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Dirhodium(II)-tetraacetate-Mediated Decomposition of Ethyldiazo- acetate and Ethyldiazomalonate in the Presence of Fullerene. A New Procedure for the Selective Synthesis of [6-6]-Closed Methanofullerenes
No full textThe reaction of C60 fullerene with carboalkoxycarbenoids generated by Rh2(OAc)4-catalyzed decomposition of α-diazoester precursors is reported. This reaction is the first example of a transition metal catalyzed carbenoid reaction with fullerene and represents a significative improvement in terms of reaction conditions, selectivity of the products obtained, and yields over previously reported methods
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