Issue 4, 2021

Characterizing the structure–activity relationships of natural products, tanshinones, reveals their mode of action in inhibiting spleen tyrosine kinase

Abstract

The cytosolic non-receptor protein kinase, spleen tyrosine kinase (SYK), is an attractive drug target in autoimmune, inflammatory disorder, and cancers indications. Here, we employed pharmacophore-based drug screening combined with biochemical assay and molecular dynamics (MD) simulations to identify and characterize inhibitors targeting SYK. The built pharmacophore model, phar-TanI, successfully identified tanshinone (TanI (IC50 = 1.72 μM)) and its analogs (TanIIA (IC50 = 3.2 μM), ST32da (IC50 = 46 μM), and ST32db (IC50 = 51 μM)) which apparently attenuated the activities of SYK in vitro. Additionally, the MD simulations followed by Ligplot analyses revealed that TanI and TanIIA interfered SYK activity through binding deeply into the active site. Besides, TanI and TanIIA mainly interact with residues L377, A400, V433, M448, M450, A451, E452, L453, G454, P455, and L501, which are functional hotspots for structure-based inhibitor optimization against SYK. The structure–activity relationships (SAR) study of the identified SYK inhibitors demonstrated that the pharmacophore model, phar-TanI is reliable and precise in screening inhibitors against SYK. This study disclosed the structure–function relationships of tanshinones from Traditional Chinese Medicine (Danshen), revealing their binding site and mode of action in inhibiting SYK and provides applicability in developing new therapeutic agents.

Graphical abstract: Characterizing the structure–activity relationships of natural products, tanshinones, reveals their mode of action in inhibiting spleen tyrosine kinase

Supplementary files

Article information

Article type
Paper
Submitted
15 Oct 2020
Accepted
05 Jan 2021
First published
14 Jan 2021
This article is Open Access
Creative Commons BY-NC license

RSC Adv., 2021,11, 2453-2461

Characterizing the structure–activity relationships of natural products, tanshinones, reveals their mode of action in inhibiting spleen tyrosine kinase

M. Tung, K. Tsai, K. Fung, M. Don and T. Tseng, RSC Adv., 2021, 11, 2453 DOI: 10.1039/D0RA08769F

This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. You can use material from this article in other publications, without requesting further permission from the RSC, provided that the correct acknowledgement is given and it is not used for commercial purposes.

To request permission to reproduce material from this article in a commercial publication, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party commercial publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements