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

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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
Volume29
Issue number8
DOIs
Publication statusPublished - Jul 21 2015

Fingerprint

Nucleotides
Ligands
X-Rays
X rays
ligands
nucleotides
Purinergic P2Y Receptor Antagonists
x rays
Piperazines
Anthraquinones
Mutagenesis
Molecular modeling
Sulfonamides
Binding sites
Molecular Dynamics Simulation
Structure-Activity Relationship
G-Protein-Coupled Receptors
GTP-Binding Proteins
Urea
Drug products

Keywords

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

ASJC Scopus subject areas

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

Cite this

Paoletta, S., Sabbadin, D., Von Kügelgen, I., Hinz, S., Katritch, V., Hoffmann, K., ... Jacobson, K. A. (2015). Modeling ligand recognition at the P2Y12 receptor in light of X-ray structural information. Journal of Computer-Aided Molecular Design, 29(8), 737-756. https://doi.org/10.1007/s10822-015-9858-z

Modeling ligand recognition at the P2Y12 receptor in light of X-ray structural information. / Paoletta, Silvia; Sabbadin, Davide; Von Kügelgen, Ivar; Hinz, Sonja; Katritch, Vsevolod; Hoffmann, Kristina; Abdelrahman, Aliaa; Straßburger, Jens; Baqi, Younis; Zhao, Qiang; Stevens, Raymond C.; Moro, Stefano; Müller, Christa E.; Jacobson, Kenneth A.

In: Journal of Computer-Aided Molecular Design, Vol. 29, No. 8, 21.07.2015, p. 737-756.

Research output: Contribution to journalArticle

Paoletta, S, Sabbadin, D, Von Kügelgen, I, Hinz, S, Katritch, V, Hoffmann, K, Abdelrahman, A, Straßburger, J, Baqi, Y, Zhao, Q, Stevens, RC, Moro, S, Müller, CE & Jacobson, KA 2015, 'Modeling ligand recognition at the P2Y12 receptor in light of X-ray structural information', Journal of Computer-Aided Molecular Design, vol. 29, no. 8, pp. 737-756. https://doi.org/10.1007/s10822-015-9858-z
Paoletta, Silvia ; Sabbadin, Davide ; Von Kügelgen, Ivar ; Hinz, Sonja ; Katritch, Vsevolod ; Hoffmann, Kristina ; Abdelrahman, Aliaa ; Straßburger, Jens ; Baqi, Younis ; Zhao, Qiang ; Stevens, Raymond C. ; Moro, Stefano ; Müller, Christa E. ; Jacobson, Kenneth A. / Modeling ligand recognition at the P2Y12 receptor in light of X-ray structural information. In: Journal of Computer-Aided Molecular Design. 2015 ; Vol. 29, No. 8. pp. 737-756.
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