Bioinformatics Guided Identification of Key genes and Docking-Supported SAR and QSAR Analysis of Cathepsin S (CTSS) Inhibitors Relevant to Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is the most widespread pathological change in diseases of the respiratory system. However, we know poorly about the molecular mechanisms and effective therapeutic approaches of ARDS. The ARDS RNA- sequencing dataset, GSE279069, was downloaded from the Gene Expression Omnibus (GEO) database. Using the DESeq2 package of r bioconductor to screen Differentially expressed genes (DEGs). Gene ontology (GO) and REACTOME pathway enrichment analysis were performed on the DEGs. Meanwhile, using the HiPPIE database and Cytoscape software to construct protein-protein interaction (PPI) network and modules. The hub gene-related miRNA-hub gene regulatory network, TF-hub gene regulatory network were constructed. Next, DrugBank database was utilized to search for alternative drugs targeting ARD hub genes. Diagnostic values of hub genes were assessed by receiver operating characteristic (ROC) curves analysis. Finally, molecular docking and QSAR analysis were performed to validate the interaction between 1q and 1r, and the hub gene Cathepsin S. 958 DEGs (479 up-regulated and 479 down-regulated) were identified from 135 ARDS patients and 74 normal control samples. These DEGs were found to be enriched for various gene ontology (GO) functions and pathways, including response to stimulus, membrane, hydrolase activity, multicellular organismal process, cell periphery, transporter activity, immune system and neuronal system. A protein-protein interaction (PPI) network was established using these 958 genes. The top hub genes (FN1, ARRB1, ENG, HTRA4, ATM, HTR2C, ELAVL2, FGB, APLNR and SIGLECL1) were acquired through calculation by the Network Analyzer plug-in in Cytoscape software. Key miRNAs (hsa-miR-30d-5p and hsa-miR-28-5p), TFs (NR0B1 and PHOX2B) and drug molecules (Zenarestat and Chlorpromazine) were predicted. Molecular docking analysis revealed that compound 1q and 1r binds to Cathepsin S with a binding energy of -7.8 kcal/mol, indicating highly stable binding. In summary, the DEGs and hub genes identified in the present investigation not only contribute to a better understanding of the molecular mechanisms underlying the progression of ARDA, but might also serve as potential new biomarkers and targets for ARDA.