25 results for "Deflorian, Francesca"
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Comparison of three GPCR structural templates for modeling of the P2Y(12) nucleotide receptor
The P2Y(12) receptor (P2Y(12)R) is an ADP-activated G protein-coupled receptor (GPCR) that is an important target for antithrombotic drugs. Three homology models of P2Y(12)R were compared, based on different GPCR structural templates: bovine rhodopsin (bRHO), human A(2A) adenosine receptor…
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Probing GPCR Structure: Adenosine and P2Y Nucleotide Receptors
The adenosine receptors (ARs) provide an example of how to accurately predict ligand recognition, even prior to the availability of a crystallographic structure. Homology modeling has been used to gain structural insight, in conjunction with site-directed mutagenesis and structure activity…
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Pharmacochemistry of the platelet purinergic receptors
Platelets contain at least five purinergic G protein-coupled receptors, e.g., the pro-aggregatory P2Y(1) and P2Y(12) receptors, a P2Y(14) receptor (GPR105) of unknown function, and anti-aggregatory A(2A) and A(2B) adenosine receptor (ARs), in addition to the ligand-gated P2X1 ion channel. Probing…
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G protein-coupled adenosine (P1) and P2Y receptors: ligand design and receptor interactions
The medicinal chemistry and pharmacology of the four subtypes of adenosine receptors (ARs) and the eight subtypes of P2Y receptors (P2YRs, activated by a range of purine and pyrimidine mono- and dinucleotides) has recently advanced significantly leading to selective ligands. X-ray crystallographic…
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Understanding Ligand Binding Selectivity in a Prototypical GPCR Family
[Image: see text] Adenosine receptors are involved in many pathological conditions and are thus promising drug targets. However, developing drugs that target this GPCR subfamily is a challenging task. A number of drug candidates fail due to lack of selectivity which results in unwanted side…
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Truncated (N)-Methanocarba Nucleosides as A(1) Adenosine Receptor Agonists and Partial Agonists: Overcoming Lack of a Recognition Element
[Image: see text] A(1) adenosine receptor (AR) agonists are neuroprotective, cardioprotective, and anxiolytic. (N)-Methanocarba adenine nucleosides designed to bind to human A(1)AR were truncated to eliminate 5′-CH(2)OH. This modification previously converted A(3)AR agonists into antagonists, but…
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Pyrazolo-triazolo-pyrimidines as adenosine receptor antagonists: A complete structure–activity profile
In the last 5 years, many efforts have been conducted searching potent and selective human A(3) adenosine antagonists. In this field several different classes of compounds, possessing very good affinity (nM range) and with a broad range of selectivity, have been proposed. Recently, our group…
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High end GPCR design: crafted ligand design and druggability analysis using protein structure, lipophilic hotspots and explicit water networks
PURPOSE: G Protein-Coupled Receptors (GPCRs) are a large family of therapeutically important proteins and as diverse X-ray structures become available it is increasingly possible to leverage structural information for rational drug design. We present herein approaches that use explicit water…
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Demystifying the three dimensional structure of G protein-coupled receptors (GPCRs) with the aid of molecular modeling
We review our recent work on adenosine receptors, a family of GPCRs; focusing our attention on A(3) adenosine receptor, we have demonstrated that the reciprocal integration of different theoretical and experimental disciplines can be very useful for the successful protein-based design of new…
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Structural Basis of the Selectivity of the β(2)-Adrenergic Receptor for Fluorinated Catecholamines
The important and diverse biological functions of adrenergic receptors, a subclass of G-protein coupled receptors (GPCRs), have made the search for compounds that selectively stimulate or inhibit the activity of different adrenergic receptor subtypes an important area of medicinal chemistry. We…
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Synthesis and Evaluation of 1,2,4-Triazolo[1,5-c]pyrimidine Derivatives as A(2A) Receptor-Selective Antagonists
Movement disorders such as Parkinson’s disease and Huntington’s disease are serious life-limiting and debilitating movement disorders. Their onset typically occurs from mid-life to late in life, and effective diagnostic techniques for detecting and following the disease course are lacking. Our goal…
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Farnesyl pyrophosphate is an endogenous antagonist to ADP-stimulated P2Y(12) receptor-mediated platelet aggregation
Farnesyl pyrophosphate (FPP) is an intermediate in cholesterol biosynthesis, and it has also been reported to activate platelet LPA (lysophosphatidic acid) receptors. The aim of this study was to investigate the role of extracellular FPP in platelet aggregation. Human platelets were studied with…
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Click Modification in the N(6) Region of A(3) Adenosine Receptor-Selective Carbocyclic Nucleosides for Dendrimeric Tethering that Preserves Pharmacophore Recognition
Adenosine derivatives were modified with alkynyl groups on N(6) substituents for linkage to carriers using Cu(I)-catalyzed click chemistry. Two parallel series, both containing a rigid North-methanocarba (bicyclo[3.1.0]hexane) ring system in place of ribose, behaved as A(3) adenosine receptor (AR)…
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Structural Sweet Spot for A(1) Adenosine Receptor Activation by Truncated (N)- Methanocarba Nucleosides: Receptor Docking and Potent Anticonvulsant Activity
A(1) adenosine receptor (AR) agonists display antiischemic and antiepileptic neuroprotective activity, but peripheral cardiovascular side effects impeded their development. SAR study of N(6)-cycloalkylmethyl 4′-truncated (N)-methanocarba-adenosines identified 10 (MRS5474, N(6)-dicyclopropylmethyl…
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Impact of protein–ligand solvation and desolvation on transition state thermodynamic properties of adenosine A(2A) ligand binding kinetics
Ligand–protein binding kinetic rates are growing in importance as parameters to consider in drug discovery and lead optimization. In this study we analysed using surface plasmon resonance (SPR) the transition state (TS) properties of a set of six adenosine A(2A) receptor inhibitors, belonging to…
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Structure-Guided Design of A(3) Adenosine Receptor-Selective Nucleosides: Combination of 2-Arylethynyl and Bicyclo[3.1.0]hexane Substitutions
(N)-Methanocarba adenosine 5′-methyluronamides containing known A(3) AR (adenosine receptor)-enhancing modifications, i.e. 2-(arylethynyl)adenine and N(6)-methyl or N(6)-(3-substituted-benzyl), were nanomolar full agonists of human (h) A(3)AR and highly selective (K(i) ~0.6 nM, N(6)-methyl…
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Evaluation of Molecular Modeling of Agonist Binding in Light of the Crystallographic Structure of an Agonist-Bound A(2A) Adenosine Receptor
Molecular modeling of agonist binding to the human A(2A) adenosine receptor (AR) was assessed and extended in light of crystallographic structures. Heterocyclic adenine nitrogens of co-crystallized agonist overlayed corresponding positions of the heterocyclic base of a bound triazolotriazine…
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Optimization of Adenosine 5′-Carboxamide Derivatives as Adenosine Receptor Agonists Using Structure-Based Ligand Design and Fragment Screening
[Image: see text] Structures of G protein-coupled receptors (GPCRs) have a proven utility in the discovery of new antagonists and inverse agonists modulating signaling of this important family of clinical targets. Applicability of active-state GPCR structures to virtual screening and rational…
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Molecular Probes for the A(2A) Adenosine Receptor Based on a Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine Scaffold
Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine derivatives such as SCH 442416 display high affinity and selectivity as antagonists for the human A(2A) adenosine receptor (AR). We extended ether-linked chain substituents at the p-position of the phenyl group using optimized O-alkylation. The…
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Alchemical Free Energy Calculations on Membrane-Associated Proteins
[Image: see text] Membrane proteins have diverse functions within cells and are well-established drug targets. The advances in membrane protein structural biology have revealed drug and lipid binding sites on membrane proteins, while computational methods such as molecular simulations can resolve…