4.7 Article

Quantitative and systems pharmacology 2. In silico polypharmacology of G protein-coupled receptor ligands via network-based approaches

Journal

PHARMACOLOGICAL RESEARCH
Volume 129, Issue -, Pages 400-413

Publisher

ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2017.11.005

Keywords

Drug-target interaction; G protein-coupled receptor; Polypharmacology; Network-based inference; Systems pharmacology; Computational approach

Funding

  1. National Key Research and Development Program [2016YFA0502304]
  2. National Natural Science Foundation of China [81673356]
  3. 111 Project [B07023]
  4. National Heart, Lung, and Blood Institute of the National Institutes of Health [K99HL138272]

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G protein-coupled receptors (GPCRs) are the largest super family with more than 800 membrane receptors. Currently, over 30% of the approved drugs target human GPCRs. However, only approximately 30 human GPCRs have been resolved three-dimensional crystal structures, which limits traditional structure-based drug discovery. Recent advances in network-based systems pharmacology approaches have demonstrated powerful strategies for identifying new targets of GPCR ligands. In this study, we proposed a network-based systems pharmacology framework for comprehensive identification of new drug-target interactions on GPCRs. Specifically, we reconstructed both global and local drug-target interaction networks for human GPCRs. Network analysis on the known drug-target networks showed rational strategies for designing new GPCR ligands and evaluating side effects of the approved GPCR drugs. We further built global and local network-based models for predicting new targets of the known GPCR ligands. The area under the receiver operating characteristic curve of more than 0.96 was obtained for the best network-based models in cross validation. In case studies, we identified that several network predicted GPCR off-targets (e.g. ADRA2A, ADRA2C and CHRM2) were associated with cardiovascular complications (e.g. bradycardia and palpitations) of the approved GPCR drugs via an integrative analysis of drug-target and off-target-adverse drug event networks. Importantly, we experimentally validated that two newly predicted compounds, AM966 and Ki16425, showed high binding affinities on prostaglandin E2 receptor EP4 subtype with IC50 = 2.67 mu M and 6.34 mu M, respectively. In summary, this study offers powerful network-based tools for identifying polypharmacology of GPCR ligands in drug discovery and development. (C) 2017 Elsevier Ltd. All rights reserved.

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