Computational identification of natural inhibitors of human neutrophil elastase as potential therapeutics for chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disorder in which human neutrophil elastase (HNE, encoded by ELANE) plays a central role in extracellular matrix degradation and airway remodeling. Despite its therapeutic relevance, no clinically approved HNE inhibitors are currently available for COPD treatment. In this study, an integrated computational strategy combining virtual screening, molecular docking, network pharmacology, and functional enrichment analysis was employed to identify potential natural inhibitors of HNE.

A library of 8747 phytochemicals from 64 medicinal plants was screened using Lipinski's rule of five, yielding 1326 drug-like candidates. Molecular docking against HNE, with Bay-85-8501 as a reference inhibitor, identified 33 compounds exhibiting binding affinities stronger than −8 kcal/mol. ADMET profiling further prioritized four lead compounds (CID-13783711, CID-344133, CID-442449449, and CID-10365741) with favorable pharmacokinetic and toxicity profiles.

Protein–protein interaction network (PPIN) analysis revealed 24 overlapping COPD-associated targets, with ELANE and CXCL8 emerging as key hub proteins interconnected with CAMP, MPO, TLR4, and MMP9, highlighting a neutrophil-driven inflammatory module. Gene Ontology enrichment indicated significant involvement in serine-type endopeptidase activity, acute inflammatory response, and bacterial stimulus pathways, while KEGG analysis identified enrichment in NF-κB, Toll-like receptor, NOD-like receptor, and IL-17 signaling pathways.

Overall, this study provides a comprehensive computational framework for identifying natural HNE inhibitors and elucidates their potential mechanistic roles within COPD-associated inflammatory networks. The identified lead compounds warrant further validation through molecular dynamics simulations and experimental studies to support their development as therapeutic candidates.