Discovery of novel serine/threonine protein phosphatase 1 inhibitors from traditional Chinese medicine through virtual screening and biological assays

Abstract

Protein phosphatase 1 (PP1) is a critical regulator of several processes, such as muscle contraction, neuronal signaling, glycogen synthesis, and cell proliferation. Dysregulation of PP1 has recently been found to be implicated in cardiac dysfunctions, which indicates that PP1 could be an attractive therapeutic target. However, discovery of PP1 inhibitors with satisfied safety and efficiency is still a challenge. Here, in order to discover potential PP1 inhibitors, compounds extracted from traditional Chinese medicine (TCM) were screened by a novel integrated virtual screening protocol including pharmacophore modeling and docking approaches. Combined with protein phosphatase inhibition assay, ZINC43060554 showed strongly inhibitory activity with IC₅₀ values of 26.78 μM. Furthermore, molecular dynamics simulation and Molecular Mechanics/Generalized Born Surface Area binding free-energy analysis were performed to examine the stability of ligand binding modes. These novel scaffolds discovered in the present study can be used for rational design of PP1 inhibitors with high affinity.

Communicated by Ramaswamy H. Sarma

Keywords:

• Protein phosphatase 1
• virtual screening
• pharmacophore model
• molecular docking
• molecular dynamics simulations

Acknowledgements

We are grateful to our colleagues for their critical reviews and constructive suggestions regarding this manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the National Science Foundation of China (No. 81573304, 81703342), Natural Science Foundation of Jiangsu (No. BK20161050) and Research Fund for Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization (ZDXM-2-1). This study was also supported by a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (2014–2017).