Integrative transcriptomic and structural analysis identifies PTGS2 as a key target in ischemic stroke associated with neuroinflammation.

Ischemic stroke is a leading cause of mortality and long-term disability worldwide, primarily driven by neuroinflammatory damage. Prostaglandin-endoperoxide synthase 2 (PTGS2), which encodes the cyclooxygenase-2 (COX-2) enzyme, plays a central role in mediating inflammatory pathways, making it a key therapeutic target in ischemic stroke. This study presents a comprehensive analysis aimed at identifying potential PTGS2 inhibitors for mitigating neuroinflammatory damage in ischemic stroke. Gene expression profiling of the GSE16561 dataset, comprising control and stroke patient samples, revealed 329 differentially expressed genes (DEGs), including PTGS2 and ZFHX3, central to neuroinflammatory and vascular remodeling pathways. Modular co-expression analysis identified distinct gene clusters associated with oxidative stress, apoptosis, and blood-brain barrier dysfunction, providing insights into molecular mechanisms underlying stroke pathology. To complement gene-level analysis, molecular clustering and feature correlation studies were performed on a dataset of compounds using PubChem and substructure descriptors. Hierarchical clustering revealed four molecular clusters, with Cluster 2 compounds (CHEMBL44468 and CHEMBL462709) showing unique features like sulfur-containing and bridged-ring systems. These descriptors were validated as contributors to molecular differentiation through t-SNE visualization and heatmap analysis. Molecular docking, dynamics, and MM-GBSA studies further highlighted the strong binding affinities of these compounds to the PTGS2 active site, supporting their potential to modulate inflammatory pathways implicated in stroke. This integrative approach, combining gene expression analysis, molecular clustering, and docking studies, underscores the potential of Cluster 2 compounds as promising candidates. This study provides a framework for advancing ischemic stroke therapeutics and targeted anti-inflammatory drug development by bridging transcriptomic insights with structural studies.