Drug Design, Development and Therapy (Apr 2023)

Virtual Screening and Biological Evaluation of Novel Low Molecular Weight Protein Tyrosine Phosphatase Inhibitor for the Treatment of Insulin Resistance

  • Feng B,
  • Dong X,
  • Liu Z,
  • Zhang J,
  • Liu H,
  • Xu Y

Journal volume & issue
Vol. Volume 17
pp. 1191 – 1201

Abstract

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Bo Feng,1,* Xu Dong,1,* Zhen Liu,2 Jie Zhang,3 Hongyu Liu,1 Yuan Xu1 1Department of Pharmacy, The Affiliated Hospital of Yangzhou University, Yangzhou, People’s Republic of China; 2Department of Neurology, The Affiliated Hospital of Yangzhou University, Yangzhou, People’s Republic of China; 3Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hongyu Liu; Yuan Xu, Department of Pharmacy, The Affiliated Hospital of Yangzhou University, Yangzhou, People’s Republic of China, Email [email protected]; [email protected]: Protein tyrosine phosphatases (PTPs) play an essential way in diseases including cancer, obesity, diabetes and autoimmune disorders. As a member of PTPs, low molecular weight PTP (LMPTP) has been a well-recognized anti-insulin resistance target in obesity. However, the number of reported LMPTP inhibitors is limited. Our research aims to discover a novel LMPTP inhibitor and evaluate its biological activity against insulin resistance.Methods: A virtual screening pipeline based on the X-ray co-crystal complex of LMPTP was constructed. Enzyme inhibition assay and cellular bioassay were used to evaluate the activity of screened compounds.Results: The screening pipeline rendered 15 potential hits from Specs chemical library. Enzyme inhibition assay identified compound F9 (AN-465/41163730) as a potential LMPTP inhibitor with a Ki value of 21.5 ± 7.3 μM. Cellular bioassay showed F9 could effectively increase the glucose consumption of HepG2 cells as a result of releasing insulin resistance by regulating PI3K-Akt pathway.Conclusion: In summary, this study presents a versatile virtual screening pipeline for potential LMPTP inhibitor discovery and provides a novel-scaffold lead compound that is worthy of further modification to get more potent LMPTP inhibitors.Graphical Abstract: Keywords: virtual screening, low molecular weight protein tyrosine phosphatase, LMPTP inhibitor, insulin resistance, molecular docking

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