Network pharmacology-guided subtractive proteomics coupled with molecular docking and molecular dynamics simulation identifies Nigella sativa as a potential anti-sepsis therapeutic

Abstract

Sepsis is a life-threatening condition caused by a dysregulated host immune response to infection, often leading to organ failure. Increasing antibiotic resistance, particularly in Streptococcus pneumoniae, highlights the urgent need for alternative therapeutic strategies. Nigella sativa, known for its anti-inflammatory and antimicrobial properties, may serve as a source of potential bioactive compounds for sepsis management. This study investigated the therapeutic potential of N. sativa phytochemicals using an integrated computational approach including network pharmacology, subtractive proteomics, molecular docking, and molecular dynamics (MD) simulation. Bioactive compounds with favorable drug-like properties were selected, and overlapping targets between N. sativa and sepsis were identified using public databases. Protein–protein interaction networks and compound–target–pathway analyses using STRING and Cytoscape identified key genes, including IL6, AKT1, TP53, PPARG, CASP3, GPX2, GPX3, and GPX6. Gene ontology, KEGG pathway analysis, and microarray datasets (GSE7065, GSE69528, and GSE46955) supported their putative involvement in sepsis. Molecular docking revealed putative strong binding affinities of alpha-tocopherol with PPARG (− 8.1 kcal/mol) and catechin with TP53 (− 7.6 kcal/mol). Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) predictions using ADMETlab 2.0 supported their pharmacokinetic suitability. Subtractive proteomics of S. pneumoniae D39 identified pathogen-specific targets, including CiaR, PTSl, and PnpR. Docking and virtual screening showed strong interactions of apigenin with CiaR (− 7.9 kcal/mol), catechin with PTSl (− 7.7 kcal/mol), and riboflavin with PnpR (− 7.2 kcal/mol). Molecular dynamics (MD) simulations suggested the putative stability of these complexes under simulated conditions. Overall, the findings suggest that N. sativa may provide dual therapeutic benefits by modulating host immune responses and targeting pathogen proteins, supporting its potential for future anti-sepsis drug development based on computational predictions that require experimental validation.