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


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.


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



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)


  1. 1.
    Koole C et al (2013) Recent advances in understanding GLP-1R (glucagon-like peptide-1 receptor) function. Biochem. Soc. Trans. 41:172–179CrossRefGoogle Scholar
  2. 2.
    Prasad-Reddy L, Isaacs D (2015) A clinical review of GLP-1 receptor agonists: efficacy and safety in diabetes and beyond. Drugs Context 4:212283CrossRefGoogle Scholar
  3. 3.
    Jazayeri A et al (2017) Crystal structure of the GLP-1 receptor bound to a peptide agonist. Nature 546:254–258CrossRefGoogle Scholar
  4. 4.
    Zhang Y et al (2017) Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein. Nature 546:248–253CrossRefGoogle Scholar
  5. 5.
    Song G et al (2017) Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators. Nature 546:312–315CrossRefGoogle Scholar
  6. 6.
    Liang YL et al (2018) Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex. Nature 555:121–125CrossRefGoogle Scholar
  7. 7.
    Knudsen LB et al (2007) Small-molecule agonists for the glucagon-like peptide 1 receptor. Proc. Natl. Acad. Sci. USA 104:937–942CrossRefGoogle Scholar
  8. 8.
    Chen D et al (2007) A nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db/db mice. Proc. Natl. Acad. Sci. USA 104:943–948CrossRefGoogle Scholar
  9. 9.
    Sloop KW (2010) Novel small molecule glucagon-like peptide-1 receptor agonist stimulates insulin secretion in rodents and from human islets. Diabetes 59:3099–3107CrossRefGoogle Scholar
  10. 10.
    Wootten D et al (2011) Modulation of the glucagon-like peptide-1 receptor signaling by naturally occurring and synthetic flavonoids. J. Pharmacol. Exp. Ther. 336:540–550CrossRefGoogle Scholar
  11. 11.
    Willard FS, Bueno AB, Sloop KW (2012) Small molecule drug discovery at the glucagon-like peptide-1 receptor. Exp. Diabetes Res. 2012:709893PubMedPubMedCentralGoogle Scholar
  12. 12.
    Morris LC et al (2014) Discovery of (S)-2-cyclopentyl-N-((1-isopropylpyrrolidin2-yl)-9-methyl-1-oxo-2,9-dihydro-1H-py rrido[3,4-b]indole-4-carboxamide (VU0453379): a novel, CNS penetrant glucagon-like peptide 1 receptor (GLP-1R) positive allosteric modulator (PAM). J. Med. Chem. 57:10192–10197CrossRefGoogle Scholar
  13. 13.
    Hollenstein K et al (2013) Structure of class B GPCR corticotropin-releasing factor receptor 1. Nature 499:438–443CrossRefGoogle Scholar
  14. 14.
    May LT, Leach K, Sexton PM, Christopoulos A (2007) Allosteric modulation of G protein-coupled receptors. Annu. Rev. Pharmacol. Toxicol. 47:1–51CrossRefGoogle Scholar
  15. 15.
    Conn PJ, Christopoulos A, Lindsley CW (2009) Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat. Rev. Drug Discov. 8:41–54CrossRefGoogle Scholar
  16. 16.
    Khoury E, Clement S, Laporte SA (2014) Allosteric and biased g protein-coupled receptor signaling regulation: potentials for new therapeutics. Front. Endocrinol. 5:68CrossRefGoogle Scholar
  17. 17.
    Bueno AB (2016) Positive allosteric modulation of the glucagon-like peptide-1 receptor by diverse electrophiles. J. Biol. Chem. 291:10700–10715CrossRefGoogle Scholar
  18. 18.
    Redij T et al (2019) Structural modeling and in silico screening of potential small molecule allosteric agonists of glucagon-like peptide 1 receptor. ACS Omega 4:961–970CrossRefGoogle Scholar
  19. 19.
    Irwin JJ, Shoichet BK (2005) ZINC—a free database of commercially available compounds for virtual screening. J. Chem. Inf. Model. 45:177–182CrossRefGoogle Scholar
  20. 20.
    Halgren TA et al. (2004) Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J. Med. Chem. 47(7), 1750–1759.CrossRefGoogle Scholar
  21. 21.
    Repasky MP et al (2012) Docking performance of the glide program as evaluated on the Astex and DUD datasets: a complete set of glide SP results and selected results for a new scoring function integrating WaterMap and glide. J. Comput. Aided Mol. Des. 26:787–799CrossRefGoogle Scholar
  22. 22.
    Wang R, Fu Y, Lai L (1997) A new atom-additive method for calculating partition coefficients. J. Chem. Inf. Comput. Sci. 37:615–621CrossRefGoogle Scholar
  23. 23.
    Lastya A, Saraswati MR, Suastika K (2014) The low level of glucagon-like peptide-1 (glp-1) is a risk factor of type 2 diabetes mellitus. BMC Res. Notes 7(1):849CrossRefGoogle Scholar
  24. 24.
    King AB, Armstrong DU, Chinnapongse S (2003) Comparison of glycemic and lipid response to pioglitazone treatment in Mexican-Americans and non-Hispanic Caucasians with type 2 diabetes. Diabetes Care 26:245–246CrossRefGoogle Scholar
  25. 25.
    Toft-Nielsen MB, Madsbad S, Holst JJ (2001) Determinants of the effectiveness of glucagon-like peptide-1 in type 2 diabetes. J. Clin. Endocrinol. Metab. 86:3853–3860CrossRefGoogle Scholar
  26. 26.
    Knop FK et al (2007) Reduced incretin effect in type 2 diabetes: cause or consequence of the diabetic state? Diabetes 56:1951–1959CrossRefGoogle Scholar
  27. 27.
    Kjems LL, Holst JJ, Volund A, Madsbad S (2003) The influence of GLP-1 on glucose-stimulated insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic subjects. Diabetes 52:380–386CrossRefGoogle Scholar
  28. 28.
    Wootten D et al (2017) Allostery and biased agonism at class B G protein-coupled receptors. Chem. Rev. 117:111–138CrossRefGoogle Scholar
  29. 29.
    Pupo AS et al (2016) Recent updates on GPCR biased agonism. Pharmacol. Res. 112:49–57CrossRefGoogle Scholar
  30. 30.
    Atwood BK et al (2011) Expression of G protein-coupled receptors and related proteins in HEK293, AtT20, BV2, and N18 cell lines as revealed by microarray analysis. BMC Genomics 12:14CrossRefGoogle Scholar
  31. 31.
    de Graaf C et al (2011) Structure-based discovery of allosteric modulators of two related class B G-protein-coupled receptors. ChemMedChem 6:2159–2169CrossRefGoogle Scholar

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

Personalised recommendations