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

Silvia Paoletta, Davide Sabbadin, Ivar Von Kügelgen, Sonja Hinz, Vsevolod Katritch, Kristina Hoffmann, Aliaa Abdelrahman, Jens Straßburger, Younis Baqi, Qiang Zhao, Raymond C. Stevens, Stefano Moro, Christa E. Müller, Kenneth A. Jacobson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)


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. Graphical Abstract: [Figure not available: see fulltext.]

Original languageEnglish
Pages (from-to)737-756
Number of pages20
JournalJournal of Computer-Aided Molecular Design
Issue number8
Publication statusPublished - Aug 14 2015


  • G protein-coupled receptors
  • Molecular modeling
  • Nucleotides
  • Purines
  • Structure-activity relationship
  • X-ray crystallographic structures

ASJC Scopus subject areas

  • Drug Discovery
  • Computer Science Applications
  • Physical and Theoretical Chemistry


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