Adenosine analogues as inhibitors of P2Y12 receptor mediated platelet aggregation

Douglass, James G.; deCamp, J. Bryan; Fulcher, E; Jones, W. Schuyler; Mahanty, Sanjoy K.; Morgan, Anna; Smirnov, Dima; Boyer, José L.; Watson, Paul S.

doi:10.1016/j.bmcl.2008.01.038

Cited by 12 publications

(2 citation statements)

References 10 publications

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“…Since P2Y 12 has been identified a promising target to antiplatelet drugs, recently many classes of ADP receptor antagonists including prasugrel, ticlopidine, ticagrelor, cangrelor, 2-alkylthio-substituted analogues, 6-amino-2-mercapto-3H-pyrimidin-4-one derivatives, piperazinyl-glutamate-pyridines/pyrimidines-based antagonists, − piperazinyl-glutamate-quinolines, − anthraquinones, adenosine analogues, piperazinyl-pyridine ureas, etc. were synthesized, some of which achieved promising inhibition potency, and others were currently in late-stage clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Combined 3D-QSAR, Molecular Docking, and Molecular Dynamics Study on Piperazinyl-Glutamate-Pyridines/Pyrimidines as Potent P2Y₁₂ Antagonists for Inhibition of Platelet Aggregation

Ming

Wang

et al. 2011

J. Chem. Inf. Model.

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An unusually large data set of 397 piperazinyl-glutamate-pyridines/pyrimidines as potent orally bioavailable P2Y(12) antagonists for inhibition of platelet aggregation was studied for the first time based on the combination of three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, and molecular dynamics (MD) methods. The comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) studies have been performed with a training set of 317 compounds, estimating three superimposition methods. The best CoMFA and CoMSIA models, derived from superimposition I, shows leave-one-out cross-validation correlation coefficients (Q(2)) of 0.571 and 0.592 as well as the conventional correlation coefficients (R(2)(ncv)) of 0.814 and 0.834, respectively. In addition, the satisfactory results, based on the bootstrapping analysis and 10-fold cross-validation, further indicate the highly statistical significance of the optimal models. The external predictive abilities of these models were evaluated using a prediction set of 80 compounds, producing the predicted correlation coefficients (R(2)(pred)) of 0.664 and 0.668, respectively. The key amino acid residues were identified by molecular docking, and the stability and rationality of the derived molecular conformations were also validated by MD simulation. The good concordance between the docking results and CoMFA/CoMSIA contour maps provides helpful clues about the rational modification of molecules in order to design more potent P2Y(12) antagonists. We hope the developed models could provide some instructions for further synthesis of highly potent P2Y(12) antagonists.

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Section: Introductionmentioning

confidence: 99%

Combined 3D-QSAR, Molecular Docking, and Molecular Dynamics Study on Piperazinyl-Glutamate-Pyridines/Pyrimidines as Potent P2Y₁₂ Antagonists for Inhibition of Platelet Aggregation

Ming

Wang

et al. 2011

J. Chem. Inf. Model.

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“…Inspire Pharmaceuticals reported monophosphate 73 (INS50589), which showed inhibition of platelet aggregation in a washed human platelet assay (IC 50 = 16 nM). Unfortunately, this compound proved unsuccessful in clinical trials as an intravenously delivered drug . Further carboxylic acid replacements for the phosphate groups were investigated, with the 2-carboxybenzyl analogue 74 ( h P2Y 12 IC 50 = 40 nM) being the most potent of this series.…”

Section: Drug-like Antagonists Of the P2y12 Receptor (P2y12r)mentioning

confidence: 99%

Drug-like Antagonists of P2Y Receptors—From Lead Identification to Drug Development

et al. 2016

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P2Y receptors are expressed in virtually all cells and tissue types and mediate an astonishing array of biological functions including platelet aggregation, smooth muscle cell proliferation and immune regulation. The P2Y receptors belong to the GPCR superfamily and are composed of eight members encoded by distinct genes that can be subdivided into two groups based on their coupling to specific G-proteins. Extensive research has been undertaken to find modulators of P2Y receptors, although to date there have only been a limited number of small molecule P2Y receptor antagonists that have been approved by drug/medicines agencies. This Perspective reviews the known P2Y receptor antagonists, highlighting oral drug-like receptor antagonists, and considers future opportunities for the development of small molecules for clinical evaluation.

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Modeling ligand recognition at the P2Y12 receptor in light of X-ray structural information

Paoletta

Sabbadin

Kügelgen

et al. 2015

J Comput Aided Mol Des

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Summary The G protein-coupled P2Y12 receptor (P2Y12R) is an important antithrombotic target and of great interest for pharmaceutical discovery. Its recently solved, highly divergent crystallographic structures in complex either with nucleotides (full or partial agonist) or with a nonnucleotide antagonist raise the question of which structure is more useful to understand ligand recognition. Therefore, we performed extensive molecular modeling studies based on these structures and mutagenesis, to predict the binding modes of major classes of P2Y12R ligands previously reported. Various nucleotide derivatives docked readily to the agonist-bound P2Y12R, but uncharged nucleotide-like antagonist ticagrelor required a hybrid receptor resembling the agonist-bound P2Y12R except for the top portion of TM6. Supervised molecular dynamics (SuMD) of ticagrelor binding indicated interactions with the extracellular regions of P2Y12R, defining possible meta-binding sites. Ureas, sulfonylureas, sulfonamides, anthraquinones and glutamic acid piperazines docked readily to the antagonist-bound P2Y12R. Docking dinucleotides at both agonist- and antagonist-bound structures suggested interactions with two P2Y12R pockets. Thus, our structure-based approach consistently rationalized the main structure-activity relationships within each ligand class, giving useful information for designing improved ligands.

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Adenosine analogues as inhibitors of P2Y12 receptor mediated platelet aggregation

Cited by 12 publications

References 10 publications

Combined 3D-QSAR, Molecular Docking, and Molecular Dynamics Study on Piperazinyl-Glutamate-Pyridines/Pyrimidines as Potent P2Y₁₂ Antagonists for Inhibition of Platelet Aggregation

Combined 3D-QSAR, Molecular Docking, and Molecular Dynamics Study on Piperazinyl-Glutamate-Pyridines/Pyrimidines as Potent P2Y₁₂ Antagonists for Inhibition of Platelet Aggregation

Drug-like Antagonists of P2Y Receptors—From Lead Identification to Drug Development

Modeling ligand recognition at the P2Y12 receptor in light of X-ray structural information

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Adenosine analogues as inhibitors of P2Y12 receptor mediated platelet aggregation

Cited by 12 publications

References 10 publications

Combined 3D-QSAR, Molecular Docking, and Molecular Dynamics Study on Piperazinyl-Glutamate-Pyridines/Pyrimidines as Potent P2Y12 Antagonists for Inhibition of Platelet Aggregation

Combined 3D-QSAR, Molecular Docking, and Molecular Dynamics Study on Piperazinyl-Glutamate-Pyridines/Pyrimidines as Potent P2Y12 Antagonists for Inhibition of Platelet Aggregation

Drug-like Antagonists of P2Y Receptors—From Lead Identification to Drug Development

Modeling ligand recognition at the P2Y12 receptor in light of X-ray structural information

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Product

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Combined 3D-QSAR, Molecular Docking, and Molecular Dynamics Study on Piperazinyl-Glutamate-Pyridines/Pyrimidines as Potent P2Y₁₂ Antagonists for Inhibition of Platelet Aggregation

Combined 3D-QSAR, Molecular Docking, and Molecular Dynamics Study on Piperazinyl-Glutamate-Pyridines/Pyrimidines as Potent P2Y₁₂ Antagonists for Inhibition of Platelet Aggregation