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

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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.

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Abbreviations

ADP:

Adenosine-5′-diphosphate

ATP:

Adenosine-5′-triphosphate

cAMP:

Cyclic adenosine monophosphate

CHO:

Chinese hamster ovary

CNS:

Central nervous system

CRE:

cAMP response element

ECFP:

Enhanced cyan fluorescent protein

EL:

Extracellular loop

GPCR:

G protein-coupled receptor

MD:

Molecular dynamics

POPC:

1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine

RMSD:

Root-mean-square deviation

SAR:

Structure–activity relationship

SuMD:

Supervised molecular dynamics

TM:

Transmembrane helix

UDP:

Uridine-5′-diphosphate

UTP:

Uridine-5′-triphosphate

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Acknowledgments

This research was supported by the National Institutes of Health (Intramural Research Program of the NIDDK and R01HL077707).

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Authors and Affiliations

  1. 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

    Silvia Paoletta & Kenneth A. Jacobson

  2. PharmaCenter Bonn, Pharmaceutical Sciences Bonn (PSB), Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany

    Sonja Hinz, Aliaa Abdelrahman, Younis Baqi & Christa E. Müller

  3. The Bridge Institute, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, 90089, USA

    Vsevolod Katritch & Raymond C. Stevens

  4. CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai, 201203, China

    Qiang Zhao

  5. Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università di Padova, via Marzolo 5, 35131, Padua, Italy

    Davide Sabbadin & Stefano Moro

  6. Department of Chemistry, Faculty of Science, Sultan Qaboos University, Muscat, Oman

    Younis Baqi

  7. Department of Pharmacology, University of Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany

    Ivar von Kügelgen, Kristina Hoffmann & Jens Straßburger

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  1. Silvia Paoletta
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  2. Davide Sabbadin
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  3. Ivar von Kügelgen
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  4. Sonja Hinz
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  7. Aliaa Abdelrahman
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  9. Younis Baqi
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  10. Qiang Zhao
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  11. Raymond C. Stevens
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  12. Stefano Moro
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  13. Christa E. Müller
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  14. Kenneth A. Jacobson
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Correspondence to Kenneth A. Jacobson.

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Paoletta, S., Sabbadin, D., von Kügelgen, I. et al. Modeling ligand recognition at the P2Y12 receptor in light of X-ray structural information. J Comput Aided Mol Des 29, 737–756 (2015). https://doi.org/10.1007/s10822-015-9858-z

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