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Journal of Computer-Aided Molecular Design

, Volume 33, Issue 11, pp 973–981 | Cite as

Discovery of a potential positive allosteric modulator of glucagon-like peptide 1 receptor through virtual screening and experimental study

  • Tejashree Redij
  • Jian Ma
  • Zhiyu Li
  • Xianxin Hua
  • Zhijun LiEmail author
Article
  • 144 Downloads

Abstract

The Glucagon-like peptide 1 receptor (GLP-1R) is a well-established target for the treatment of type 2 diabetes and GLP-1R agonist-based therapies represent an effective approach which results in several GLP-1 analog drugs. However, the development of nonpeptidic agonist drugs targeting GLP-1R remains unsuccessful. A promising strategy aims to develop orally bioavailable, small-molecule positive allosteric modulators of GLP1-1R. Taking advantage of the recently reported cryo-EM structure of GLP-1R at its active state, we have performed structure-based screening studies which include potential allosteric binding site prediction and in silico screening of drug-like compounds, and conducted in vitro testing and site-specific mutagenesis studies. One compound with low molecular weight was confirmed as a positive allosteric modulator of GLP-1R as it enhances GLP-1′s affinity and efficacy to human GLP-1R in a dose dependent manner. This compound also stimulates insulin secretion synergistically with GLP-1. With the molecular weight of 399, this compound represents one of the smallest known GLP-1R PAMs, and demonstrates other favorable drug-like properties. Site-specific mutagenesis studies confirmed that the binding site of this compound partially overlaps with that of a known antagonist in the transmembrane domain. These results demonstrate that structure-based approach is useful for discovering nonpeptidic allosteric modulators of GLP-1R and the compound reported here is valuable for further drug development.

Keywords

Virtual screening Positive allosteric modulator Glucagon-like peptide 1 receptor Type-2 diabetes 

Notes

Acknowledgements

We thank Dr. Raymond C. Stevens at ShanghaiTech University for sharing with us plasmids of human GLP-1R mutants S352A, V332W and T355A. The first two mutants were used in this work. We thank Dr. James A. McKee for helping prepare Fig. 1 and the figure of the chemical structure of compound C-1. Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR001878. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was supported in part by the Institute for Translational Medicine and Therapeutics' (ITMAT) Transdisciplinary Program in Translational Medicine and Therapeutics at University of Pennsylvania.

Supplementary material

10822_2019_254_MOESM1_ESM.docx (896 kb)
Supplementary file1 (DOCX 895 kb)

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Biological SciencesUniversity of the Sciences in PhiladelphiaPhiladelphiaUSA
  2. 2.Department of Chemistry & BiochemistryUniversity of the Sciences in PhiladelphiaPhiladelphiaUSA
  3. 3.Department of Pharmaceutical SciencesUniversity of the Sciences in PhiladelphiaPhiladelphiaUSA
  4. 4.Department of Cancer Biology, Institute for Diabetes, Obesity, and MetabolismUniversity of Pennsylvania Perelman School of MedicinePhiladelphiaUSA

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