Screening of Phytocompounds Against the NF-kB Pathway Genes and Lung Elevated Proteins Associated with Acute Respiratory Distress Syndrome.

Abstract

Introduction: Acute Respiratory Distress Syndrome (ARDS) is the pathophysiologic state of the inflammatory response to lung injury characterized by alveolar epithelial cell damage and increased cytokine production and accumulation in the lungs.

Objectives: The current study was performed to identify the molecular mechanisms of ARDS related to the proteins elevated in the lung (PEL) and NF-κB pathway regulatory genes (GRNF). In addition, the phytocompounds were screened to inhibit the representative target genes and proteins associated with ARDS.

Materials and methods: We implemented STRING v11.5 and Network Analyst 3.0 to construct the protein-protein interactions (PPI) network. CytoScape v3.8.2 and DisGeNet v7.3.0 were utilized to visualize and identify genes involved in respiratory diseases. The Cytohubba module was utilized to identify the hub genes from the constructed PPI network. Autodock Vina and Discovery Studio Visualizer v19.1.0.1828 were utilized for the molecular docking analysis.

Results: The PPI network was constructed with the GRNF genes. Fifty-four genes are identified as biomarkers involved in respiratory diseases (BMRD). About 191 PEL were identified from the human protein atlas database and constructed the PPI network. The interactions between the PPI network of BMRD and PEL were analyzed. The top 100 hub genes and the signaling genes were identified. Based on the identified signaling genes through the PPI network of BMRD and PEL, the metabolic pathway was elucidated, which causes ARDS via NF-κB activation. The ARDS targets (ACVRL1, IKKβ, ITGAL, ITGB2, TGFβR1, and TGFβR2) were selected for the molecular docking study. One hundred and thirty-five chemical compounds from Allium sativum, Alstonia scholaris, Ammi visnaga, Artemisia vulgaris Linn., Houttuynia cordata, and Ocimum gratissimum Linn. were retrieved and used for docking against selected ARDS targets. Among them, genkdaphine from A. sativum inhibited ACVRL1 (binding affinity of -9.2 kcal/mol, and RMSD of 2.607Å), ITGAL (binding affinity of -9.1 kcal/mol, and RMSD of 1.69Å), ITGB2 (binding affinity of -7.9 kcal/mol, and RMSD of 2.184Å), TGFβRI (binding affinity of -8.5 kcal/mol, and RMSD of 1.807Å), and TGFβRII (binding affinity of -8.2 kcal/mol, and RMSD of 1.647Å). Edulisin III from A. visnaga inhibited the IKKβ (binding affinity of -7.4 kcal/mol, and RMSD of 2.223Å).

Conclusion: Genkdaphine and edulisin III may be the therapeutics for treating ARDS. However, further studies are needed to warrant the benefits of genkdaphine and edulisin III in treating ARDS. The study's findings may aid in developing new therapeutic approaches to improve the health status of ARDS-affected patients.