Discovery of inhibitors targeting protein tyrosine phosphatase 1B using a combined virtual screening approach.

Abstract

Protein tyrosine phosphatase 1B (PTP1B) acts as a therapeutic target for type 2 diabetes. However, the major challenges of PTP1B drug discovery are the poor selectivity and the weak oral bioavailability. In this study, we performed a combined virtual screening approach including multicomplex pharmacophore, molecular docking-based screening, van der Waals energy normalization, pose scaling factor, ADMET evaluation, and molecular dynamics simulation to select PTP1B inhibitors from three databases (PubChem, ChEMBL, and ZINC). We identified three potential PTP1B inhibitors, compounds 1, 4, and 5, with favorable binding energy and good oral bioavailability. The energetic and geometrical analyses show that the three compounds are stably bound to PTP1B, via occupying both the catalytic site (site A) and the proximal noncatalytic site (site B or C). Such occupancy may improve the selectivity. This work not only provided a feasible virtual screening protocol, but also suggested three potential PTP1B inhibitors for the treatment of type 2 diabetes.

• Authors: Dan Zhao, Lu Sun, Shijun Zhong
• Journal: Molecular diversity (Mol Divers) Vol. 26 Issue 4 Pg. 2159-2174 (Aug 2022) ISSN: 1573-501X [Electronic] Netherlands
• PMID: 34655403 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.

Chemical References

• Enzyme Inhibitors
• Protein Tyrosine Phosphatase, Non-Receptor Type 1

Topics

• Diabetes Mellitus, Type 2 (drug therapy)
• Enzyme Inhibitors (chemistry)
• Humans
• Molecular Docking Simulation
• Molecular Dynamics Simulation
• Protein Tyrosine Phosphatase, Non-Receptor Type 1 (antagonists & inhibitors)