Identification of the novel natural product inhibitors of SHP2 from the plant Toona sinensis: In vitro and in silico study

Ji-Feng Zhao; Rong-Shen Wang; Sheng-Ze Lu; Xiao-Jing Guo; Ying Chen; Li-Hua Li; Chuan-Hua Ding; Wen-Shan Liu

doi:10.1016/j.ijbiomac.2022.09.042

Identification of the novel natural product inhibitors of SHP2 from the plant Toona sinensis: In vitro and in silico study

Int J Biol Macromol. 2022 Nov 30:221:679-690. doi: 10.1016/j.ijbiomac.2022.09.042. Epub 2022 Sep 9.

Authors

Ji-Feng Zhao¹, Rong-Shen Wang², Sheng-Ze Lu², Xiao-Jing Guo³, Ying Chen², Li-Hua Li⁴, Chuan-Hua Ding⁵, Wen-Shan Liu⁶

Affiliations

¹ Shandong Key Laboratory of Clinical Applied Pharmacology, Department of Pharmacy, Affiliated Hospital of Weifang Medical University, Weifang 261041, Shandong Province, China; Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang 261041, Shandong Province, China.
² School of Pharmacy, Weifang Medical University, Weifang 261053, Shandong Province, China.
³ Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang 261041, Shandong Province, China.
⁴ Eye Center, Affiliated Hospital of Weifang Medical University, Weifang 261041, Shandong Province, China. Electronic address: [email protected].
⁵ Shandong Key Laboratory of Clinical Applied Pharmacology, Department of Pharmacy, Affiliated Hospital of Weifang Medical University, Weifang 261041, Shandong Province, China. Electronic address: [email protected].
⁶ Shandong Key Laboratory of Clinical Applied Pharmacology, Department of Pharmacy, Affiliated Hospital of Weifang Medical University, Weifang 261041, Shandong Province, China; Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang 261041, Shandong Province, China. Electronic address: [email protected].

PMID: 36096249
DOI: 10.1016/j.ijbiomac.2022.09.042

Abstract

In this study, we tested the inhibitory activity of 45 natural products extracted from the plant Toona sinensis on SHP2 protein, and identified four natural product inhibitors. The natural product 1,2,3,6-Tetragalloylglucose (A-1) was first reported as a competitive inhibitor of SHP2, with an IC₅₀ value of 0.20 ± 0.029 μM and the selectivity of 1.8-fold and 4.35-fold to high homologous proteins SHP1 and PTP1B, respectively. Compound A-1 also showed high inhibitory activity on SHP2-E76K and SHP2-E76A mutants, with IC₅₀ values of 0.95 ± 0.21 μM and 0.29 ± 0.045 μM, respectively. Cell viability assay showed that compound A-1 could inhibit the proliferation of a variety of cancer cells. Apoptosis assay showed that compound A-1 could effectively induce apoptosis of KRAS^G12C-mut NCI-H23 and KRAS^G12S-mut A549 cells. Western blot assay showed that compound A-1 could down regulate the phosphorylation levels of Erk1/2 and Akt in NCI-H23 and A549 cells. Molecular docking showed that compound A-1 could effectively dock to the catalytic active region of SHP2. Molecular dynamics simulation explored the effect of compound A-1 on SHP2, revealing the deep-seated binding mechanism. This study would provide valuable clues for the development of SHP2 and its mutant inhibitors.

Keywords: Activity evaluation; MD simulation; Molecular docking; SHP2 inhibitors; Toona sinensis.

MeSH terms

Biological Products* / pharmacology
Enzyme Inhibitors / chemistry
Molecular Docking Simulation
Protein Tyrosine Phosphatase, Non-Receptor Type 11* / chemistry
Protein Tyrosine Phosphatase, Non-Receptor Type 11* / genetics
Proto-Oncogene Proteins p21(ras) / metabolism
Toona

Substances

Protein Tyrosine Phosphatase, Non-Receptor Type 11
Enzyme Inhibitors
Biological Products
Proto-Oncogene Proteins p21(ras)