Integrated network pharmacology and molecular docking based insights into transient receptor potential melastatin3 regulatory mechanism in COPD.

Abstract

Chronic obstructive pulmonary disease (COPD) is a multifactorial airway disorder characterized by chronic inflammation, epithelial dysfunction, and dysregulated intracellular signaling. Transient receptor potential melastatin 3 (TRPM3), a Ca²⁺ permeable ion channel has emerged as a potential regulator of inflammatory and survival pathways, however, its therapeutic relevance in COPD remains poorly understood. The present study integrates network pharmacology and molecular docking to identify putative targets of TRPM3 agonists CIM0216, pregnenolone sulfate (preg sulfate), and nifedipine in COPD. A total of 2442 unique COPD associated genes were identified and integrated with predicted TRPM3 agonist targets revealing 20, 28, and 38 common targets for CIM0216, preg sulfate, and nifedipine, respectively. Enrichment analyses highlighted EGFR tyrosine kinase inhibitor resistance and PI3K/AKT signaling as key COPD related pathways which also correlated with major TFs. Further, AKT1, JAK2, and PTGS2 were identified as central hub genes, particularly associated with CIM0216 and nifedipine. No common hub genes were identified among all three TRPM3 agonists, nor between the CIM0216-preg sulfate and nifedipine-preg sulfate combinations. The hub genes were validated through GEO dataset (GSE57148). The identified miRNAs form a dense regulatory network controlling inflammatory, proliferative, and immune signaling pathways through key transcription factors, underscoring the importance of miRNA-mediated regulation in COPD progression. Molecular docking revealed that CIM0216 exhibited strong binding affinity towards TRPM3 (ΔG =  - 8.6 kcal/mol with 3 hydrogen bonds), AKT1 (ΔG =  - 10.8 kcal/mol with 4 hydrogen bonds), JAK2 (ΔG =  - 9.0 kcal/mol with 4 hydrogen bonds), and PTGS2 (ΔG =  - 9.7 kcal/mol with 6 hydrogen bonds) as compared with nifedipine which showed moderate affinity towards TRPM3 (ΔG =  - 7.1 kcal/mol and 6 hydrogen bonds), AKT1 (ΔG =  - 7.3 kcal/mol and 3 hydrogen bonds), JAK2 (ΔG =  - 6.4 kcal/mol and 2 hydrogen bonds), and PTGS2 (ΔG =  - 7.6 kcal/mol and 11 hydrogen bonds), supporting its potential for effective modulation of COPD associated signaling pathways. The study predicts that CIM0216 might act as a potential multi-target agonist of key inflammatory and survival pathways implicated in COPD. The findings propose a mechanistic insight into TRPM3-mediated signaling and support further experimental validation of TRPM3 agonists as novel therapeutic candidates for COPD.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-026-00707-3.