ArticleJournal of medicinal chemistry2007
Molecular modeling of the human P2Y2 receptor and design of a selective agonist, 2'-amino-2'-deoxy-2-thiouridine 5'-triphosphate.
Article in Journal of medicinal chemistry, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 48 citations in OpenAlex.
- Pharmacological characterization of P2Y receptor subtypes - an update.Purinergic signalling · 2024Review
- An emerging master inducer and regulator for epithelial-mesenchymal transition and tumor metastasis: extracellular and intracellular ATP and its molecular functions and therapeutic potential.Cancer cell international · 2023Review
- Role of the Purinergic P2Y2 Receptor in Pulmonary Hypertension.International journal of environmental research and public health · 2021Review
- 2-Thiouracil deprived of thiocarbonyl function preferentially base pairs with guanine rather than adenine in RNA and DNA duplexes.Nucleic acids research · 2015Article
- Synthesis of extended uridine phosphonates derived from an allosteric P2Y2 receptor ligand.Molecules (Basel, Switzerland) · 2014Article
- Extracellular nucleotides inhibit oxalate transport by human intestinal Caco-2-BBe cells through PKC-δ activation.American journal of physiology. Cell physiology · 2013Article
- Structure-based approaches to ligands for G-protein-coupled adenosine and P2Y receptors, from small molecules to nanoconjugates.Journal of medicinal chemistry · 2013Review
- Molecular Structure of P2Y Receptors: Mutagenesis, Modeling, and Chemical Probes.Wiley interdisciplinary reviews. Membrane transport and signaling · 2012Article
- G protein-coupled adenosine (P1) and P2Y receptors: ligand design and receptor interactions.Purinergic signalling · 2012Review
- Synthesis and P2Y₂ receptor agonist activities of uridine 5'-phosphonate analogues.Bioorganic & medicinal chemistry · 2012Article
- Pyrimidine nucleotides with 4-alkyloxyimino and terminal tetraphosphate δ-ester modifications as selective agonists of the P2Y(4) receptor.Journal of medicinal chemistry · 2011Article
- P2Y nucleotide receptors: promise of therapeutic applications.Drug discovery today · 2010Review
- Purinergic mechanisms in breast cancer support intravasation, extravasation and angiogenesis.Cancer letters · 2010Review
- Toward the three-dimensional structure and lysophosphatidic acid binding characteristics of the LPA(4)/p2y(9)/GPR23 receptor: a homology modeling study.Journal of molecular graphics & modelling · 2009Article
- Synthesis and P2Y receptor activity of nucleoside 5'-phosphonate derivatives.Bioorganic & medicinal chemistry letters · 2009Article
- Development of selective agonists and antagonists of P2Y receptors.Purinergic signalling · 2009Article
- Synthesis and potency of novel uracil nucleotides and derivatives as P2Y2 and P2Y6 receptor agonists.Bioorganic & medicinal chemistry · 2008Article
- UDP is a competitive antagonist at the human P2Y14 receptor.The Journal of pharmacology and experimental therapeutics · 2008Article
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
A rhodopsin-based homology model of the nucleotide-activated human P2Y2 receptor, including loops, termini, and phospholipids, was optimized with the Monte Carlo multiple minimum conformational search routine. Docked uridine 5'-triphosphate (UTP) formed a nucleobase pi-pi complex with conserved Phe3.32. Selectivity-enhancing 2'-amino-2'-deoxy substitution interacted through pi-hydrogen-bonding with aromatic Phe6.51 and Tyr3.33. A "sequential ligand composition" approach for docking the flexible dinucleotide agonist Up4U demonstrated a shift of conserved cationic Arg3.29 from the UTP gamma position to the delta position of Up4U and Up4 ribose. Synthesized nucleotides were tested as agonists at human P2Y receptors expressed in 1321N1 astrocytoma cells. 2'-Amino and 2-thio modifications were synergized to enhance potency and selectivity; compound 8 (EC50 = 8 nM) was 300-fold P2Y2-selective versus P2Y4. 2'-Amine acetylation reduced potency, and trifluoroacetylation produced intermediate potency. 5-Amino nucleobase substitution did not enhance P2Y2 potency through a predicted hydrophilic interaction possibly because of destabilization of the receptor-favored Northern conformation of ribose. This detailed view of P2Y2 receptor recognition suggests mutations for model validation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.