Identification of natural product inhibitors of PTP1B based on high-throughput virtual screening strategy: In silico, in vitro and in vivo studies

Int J Biol Macromol. 2023 Jul 15:243:125292. doi: 10.1016/j.ijbiomac.2023.125292. Epub 2023 Jun 9.

Abstract

Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of the insulin signaling pathway, which is a potential therapeutic target for the treatment of type 2 diabetes mellitus (T2DM). In this study, we identified several PTP1B inhibitors with high activity by using high-throughput virtual screening and in vitro enzyme inhibition activity verification strategies. Among them, baicalin was first reported as a selective mixed inhibitor of PTP1B, with IC50 value of 3.87 ± 0.45 μM, and its inhibitory activity against homologous proteins TCPTP, SHP2, and SHP1 exceeded 50 μM. Molecular docking study found that baicalin and PTP1B could bind stably, and revealed that baicalin had a dual inhibitory effect. Cell experiments showed that baicalin was almost non-toxic and could significantly enhance the phosphorylation of IRS-1 in C2C12 myotube cells. Animal experiments showed that baicalin could significantly reduce the blood sugar of STZ-induced diabetic mice models, and had a liver protective effect. In conclusion, this study can provide new ideas for the development of PTP1B selective inhibitors.

Keywords: Activity; Molecular docking; Natural product; PTP1B inhibitor; Selectivity.

MeSH terms

  • Animals
  • Diabetes Mellitus, Experimental* / drug therapy
  • Diabetes Mellitus, Type 2* / drug therapy
  • Enzyme Inhibitors / metabolism
  • Insulin / metabolism
  • Mice
  • Molecular Docking Simulation
  • Phosphoric Monoester Hydrolases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1

Substances

  • Phosphoric Monoester Hydrolases
  • Insulin
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Enzyme Inhibitors