Integrative Genomic and Computational Drug Discovery Approach to Unveil Key Pathways and Therapeutic Targets in Coronary Artery Disease

Coronary artery disease (CAD) is the most common cardiovascular disorder and the leading cause of heart-related deaths in world. Increasing molecular targets have been discovered for CAD and CAD-related complications prognosis and therapy. However, there is still an urgent need to identify novel biomarkers. Therefore, we evaluated biomarkers that might help the diagnosis and treatment of CAD and CAD-related complications. We searched next generation sequencing (NGS) dataset (GSE202625) and identified differentially expressed genes (DEGs) by comparing CAD and normal control samples using DESeq2. Gene ontology (GO) and pathway enrichment analyses of the DEGs were performed using the g:Profiler online database. The protein-protein interaction (PPI) network and modules were constructed and analyzed. MiRNA-hub gene regulatory network, TF-hub gene regulatory network and drug-hub gene interaction network constructed and analysis were performed to use to predict hub genes, miRNAs, TFs and drug molecules. Receiver operating characteristic (ROC) curve analysis was used to predict the diagnostic effectiveness of the hub genes. Finally, molecular docking and ADMET studies were performed for phytoconstituents. A total of 118 DEGs (479 up regulated genes and 479 down regulated genes) were detected. The GO enrichment analysis indicated that the DEGs most significantly enriched in cellular response to stimulus and biosynthetic process. The REACTOME pathway enrichment analysis revealed that the DEGs were most significantly enriched in immune system and eukaryotic translation elongation. PPI network, modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network analysis demonstrated that EGR1, SIRT1, STAT1, LRRK2, HIF1A, CSNK2B, RPS3, RPS2, RPS4X and HDAC11 were the hub genes. Drug molecules were predicted including Resveratrol, Methyltrienolone, Sevoflurane and Omacetaxinemepesuccinate for treatment of CAD. Molecular docking analysis revealed that Isocryptomerin was the main active compounds with good binding activities to the SIRT1 and ERG1. On the whole, the findings of this study enhance our understanding of the potential molecular mechanisms of CAD and CAD-related complications, and provide potential targets for further research.