Modeling ligand recognition at the P2Y(12) receptor in light of X-ray structural information

doi:10.1007/s10822-015-9858-z

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	Modeling ligand recognition at the P2Y(12) receptor in light of X-ray structural information
	Paoletta, Silvia 4; Sabbadin, Davide 1; von Kuegelgen, Ivar 5; Hinz, Sonja 3; Katritch, Vsevolod 2; Hoffmann, Kristina 5; Abdelrahman, Aliaa 3; Strassburger, Jens 5; Baqi, Younis 3,6; Zhao, Qiang7
刊名	JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
	2015-08
卷号	29 期号:8 页码:737-756
关键词	G protein-coupled receptors Purines Molecular modeling Nucleotides Structure-activity relationship X-ray crystallographic structures
ISSN号	0920-654X
DOI	10.1007/s10822-015-9858-z
文献子类	Article
英文摘要	The G protein-coupled P2Y(12) receptor (P2Y(12)R) 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 P2Y(12)R ligands previously reported. Various nucleotide derivatives docked readily to the agonist-bound P2Y(12)R, but uncharged nucleotide-like antagonist ticagrelor required a hybrid receptor resembling the agonist-bound P2Y(12)R except for the top portion of TM6. Supervised molecular dynamics (SuMD) of ticagrelor binding indicated interactions with the extracellular regions of P2Y(12)R, defining possible meta-binding sites. Ureas, sulfonylureas, sulfonamides, anthraquinones and glutamic acid piperazines docked readily to the antagonist-bound P2Y(12)R. Docking dinucleotides at both agonist- and antagonist-bound structures suggested interactions with two P2Y(12)R pockets. Thus, our structure-based approach consistently rationalized the main structure-activity relationships within each ligand class, giving useful information for designing improved ligands.
资助项目	National Institutes of Health (Intramural Research Program of NIDDK)[R01HL077707]
WOS关键词	PIPERAZINYL-GLUTAMATE-PYRIDINES ; HUMAN PLATELET P2Y(12)-RECEPTOR ; POTENT ANTAGONISTS ; P2Y RECEPTORS ; HIGH-AFFINITY ; AGGREGATION ; ADENOSINE ; IDENTIFICATION ; NUCLEOTIDES ; INHIBITION
WOS研究方向	Biochemistry & Molecular Biology ; Biophysics ; Computer Science
语种	英语
出版者	SPRINGER
WOS记录号	WOS:000359535600006
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276450]
专题	药物靶标结构与功能中心
通讯作者	Jacobson, Kenneth A.
作者单位	1.Univ Padua, Dipartimento Sci Farmaco, MMS, I-35131 Padua, Italy; 2.Univ So Calif, Bridge Inst, Dornsife Coll Letters Arts & Sci, Los Angeles, CA 90089 USA; 3.Univ Bonn, Pharmaceut Inst Pharmaceut Chem 1, PharmaCtr Bonn, Pharmaceut Sci Bonn, D-53121 Bonn, Germany; 4.NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA; 5.Univ Bonn, Dept Pharmacol, D-53127 Bonn, Germany 6.Sultan Qaboos Univ, Fac Sci, Dept Chem, Muscat, Oman; 7.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Paoletta, Silvia,Sabbadin, Davide,von Kuegelgen, Ivar,et al. Modeling ligand recognition at the P2Y(12) receptor in light of X-ray structural information[J]. JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN,2015,29(8):737-756.
APA	Paoletta, Silvia.,Sabbadin, Davide.,von Kuegelgen, Ivar.,Hinz, Sonja.,Katritch, Vsevolod.,...&Jacobson, Kenneth A..(2015).Modeling ligand recognition at the P2Y(12) receptor in light of X-ray structural information.JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN,29(8),737-756.
MLA	Paoletta, Silvia,et al."Modeling ligand recognition at the P2Y(12) receptor in light of X-ray structural information".JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN 29.8(2015):737-756.