Identification of Salvianolic acid A as a potent inhibitor of PDEs to enhance proliferation of human neural stem cells

IF 4 2区化学 Q2 CHEMISTRY, PHYSICAL

Journal of Molecular Structure Pub Date : 2024-11-28 DOI:10.1016/j.molstruc.2024.140905

Ya-Lin Li , Jun Mao , Xiu-Fen Tian , Hao Song , Ji-Xia Ren

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Abstract

The inhibition of phosphodiesterases (PDEs) is a promising therapeutic strategy for treating central nervous system (CNS) disorders due to its capacity to facilitate neuroplasticity. Salvianolic acid A (SAA) shows promise in treating CNS disorders, but its specific targets are still unclear. This study has discovered that SAA directly targets PDEs to promote the proliferation of neural stem cells (NSCs). A pharmacophore model for PDE9 inhibitors was developed and validated to screen a compound database, leading to the discovery of SAA as an active agent. Further investigation into the anti-PDEs activity of SAA has revealed that it is a broad-spectrum PDEs inhibitor, with IC₅₀ values of 28.26, 34.18, and 31.68 µM for PDE4, PDE5, and PDE9, respectively. Furthermore, the proliferation of human NSCs (H9) was significantly enhanced by 30–90 µM SAA. This study also provides comprehensive elucidations of signaling pathways associated with direct targeting of PDEs for neuroplasticity in stroke. Furthermore, molecular dynamics (MD) simulations revealed that SAA effectively interacts with the crucial amino acid residues of PDE9. The decomposition of binding free energy for acid residues offers further insight into the interactions between SAA and these key amino acids, thus providing more information for understanding the mechanism of SAA bound to PDE9.

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来源期刊

Journal of Molecular Structure 化学-物理化学

CiteScore

7.10

自引率

15.80%

发文量

2384

审稿时长

45 days

期刊介绍： The Journal of Molecular Structure is dedicated to the publication of full-length articles and review papers, providing important new structural information on all types of chemical species including: • Stable and unstable molecules in all types of environments (vapour, molecular beam, liquid, solution, liquid crystal, solid state, matrix-isolated, surface-absorbed etc.) • Chemical intermediates • Molecules in excited states • Biological molecules • Polymers. The methods used may include any combination of spectroscopic and non-spectroscopic techniques, for example: • Infrared spectroscopy (mid, far, near) • Raman spectroscopy and non-linear Raman methods (CARS, etc.) • Electronic absorption spectroscopy • Optical rotatory dispersion and circular dichroism • Fluorescence and phosphorescence techniques • Electron spectroscopies (PES, XPS), EXAFS, etc. • Microwave spectroscopy • Electron diffraction • NMR and ESR spectroscopies • Mössbauer spectroscopy • X-ray crystallography • Charge Density Analyses • Computational Studies (supplementing experimental methods) We encourage publications combining theoretical and experimental approaches. The structural insights gained by the studies should be correlated with the properties, activity and/ or reactivity of the molecule under investigation and the relevance of this molecule and its implications should be discussed.