title: Modeling ligand recognition at the P2Y12 receptor in light of X-ray structural information.
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.
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg. 8A, Rm. B1A-19, LBC, NIH, NIDDK, Bethesda, MD, 20892-0810, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Paoletta
authors.forename: Davide
authors.initials: D
authors.lastname: Sabbadin
authors.forename: Ivar
authors.initials: I
authors.lastname: von Kügelgen
authors.forename: Sonja
authors.initials: S
authors.lastname: Hinz
authors.forename: Vsevolod
authors.initials: V
authors.lastname: Katritch
authors.forename: Kristina
authors.initials: K
authors.lastname: Hoffmann
authors.forename: Aliaa
authors.initials: A
authors.lastname: Abdelrahman
authors.forename: Jens
authors.initials: J
authors.lastname: Straßburger
authors.forename: Younis
authors.initials: Y
authors.lastname: Baqi
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhao
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
mesh_terms: D000880:Anthraquinones / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation / Q000379:methods*; D056004:Molecular Dynamics Simulation; D009711:Nucleotides / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D058912:Purinergic P2Y Receptor Agonists / Q000737:chemistry* / Q000378:metabolism; D058921:Purinergic P2Y Receptor Antagonists / Q000737:chemistry* / Q000378:metabolism; D058925:Receptors, Purinergic P2Y12 / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism
chemical_list: D000880:Anthraquinones; D008024:Ligands; D009711:Nucleotides; D058912:Purinergic P2Y Receptor Agonists; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D013449:Sulfonamides