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<p>Protein-tyrosine phosphatase-2 (SHP-2) has become a new target in the study of type 2 diabetes mellitus (T2DM). Currently, there are no marketed drugs targeting SHP-2 to study T2DM caused by insulin resistance. Therefore, this study screened out SHP-2 inhibitors with potential inhibitory activity from 2 million compounds, combined with ADME/T, Lipinski &amp;Veber rules, molecular docking and molecular dynamics simulation. It is understood that the mechanism of action to inhibit the activity of SHP-2 protein by compounds is mainly protein amino acid residues PHE-113, GLU-250, LEU-254, GLN-257, PRO-491, and GLN-495 bind to ligands to produce stable conformation. Finally, a series of in vitro preliminary evaluation experiments were conducted to verify the primary activity of the lead compounds. It provides a meaningful reference for the future study of SHP-2 inhibitors with better efficacy, safety, drug-like, bioavailability and drug resistance.</p> Graphical Abstract <p></p>

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Computational insights and activity evaluation of novel SHP-2 inhibitors for targeting type 2 diabetes mellitus

  • 期刊论文

  • 发表日期：

    2025年9月4日

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  • Rong Liu,
  • Liang Zou,
  • Maoqi Wang,
  • Yueyue He,
  • Mao Shu

摘要

Protein-tyrosine phosphatase-2 (SHP-2) has become a new target in the study of type 2 diabetes mellitus (T2DM). Currently, there are no marketed drugs targeting SHP-2 to study T2DM caused by insulin resistance. Therefore, this study screened out SHP-2 inhibitors with potential inhibitory activity from 2 million compounds, combined with ADME/T, Lipinski &Veber rules, molecular docking and molecular dynamics simulation. It is understood that the mechanism of action to inhibit the activity of SHP-2 protein by compounds is mainly protein amino acid residues PHE-113, GLU-250, LEU-254, GLN-257, PRO-491, and GLN-495 bind to ligands to produce stable conformation. Finally, a series of in vitro preliminary evaluation experiments were conducted to verify the primary activity of the lead compounds. It provides a meaningful reference for the future study of SHP-2 inhibitors with better efficacy, safety, drug-like, bioavailability and drug resistance.

Graphical Abstract