Breaking the cytokine storm: An in-silico study of bamboo shoot sterols as natural TNF-α brakes in severe Dengue

Abstract

Severe dengue is primarily driven by cytokine storm and increased vascular permeability. Tumor necrosis factor-alpha (TNF-α), a key proinflammatory cytokine plays a central role in this process by promoting endothelial dysfunction and amplifying the cytokine storm. TNF-α activates downstream signaling by binding three receptor molecules. Currently, dengue has no approved antiviral treatments, with clinical care limited to supportive measures. Therefore, modulating TNF-α activity presents a promising therapeutic strategy for severe dengue intervention. Recent advances have demonstrated the potential of small molecules, such as A7A, to inhibit TNF-α by stabilizing an asymmetric conformation of the trimer. This conformation restricts receptor recruitment to two subunits, thereby impairing TNF α signaling. Traditional Sri Lankan medicine advocates the use of juice of juvenile shoots of Bambusa vulgaris as a treatment for dengue. This study explores the inhibitory potential of phytochemicals from Bambusa vulgaris to modulate TNF-α function. A total of 22 phytochemicals from juvenile Bambusa vulgaris shoots were identified through literature and subjected to in silico ADMET screening using SwissADME and pkCSM. Compounds compliant with Lipinski’s rule of five were selected for further analysis. The crystal structure of TNF-α in its asymmetric, ligand-stabilized form (PDB ID: 6OP0) was subjected to 1000 ns molecular dynamics (MD) simulations using CHARMM36m forcefield in GROMACS (version 2024.1) to obtain a stable protein conformation for docking studies. Molecular docking studies were conducted using AutoDock Vina (Version v1.2.5). Several sterols—ergosterol, β sitosterol, campesterol, stigmasterol, and stigmastanol—demonstrated strong binding affinities ranging from –12.4 to –12.9 kcal/mol, surpassing that of the positive control A7A. These hits were further validated via 1000 ns MD simulations. This study underscores the potential of Bambusa vulgaris phytochemicals, particularly sterols, as natural TNF-α inhibitors. The findings provide a foundation for the development of novel, dietary interventions targeting TNF-α in the management of severe dengue. Although the binding affinities observed are promising, further experimental studies are required to confirm the inhibitory potential of these sterols against TNF-α.