Nootkatone as a multi-target modulator of the PD-L1/PD-1 signaling in pancreatic cancer: network pharmacology, docking, molecular dynamics, and DFT analysis.

Pancreatic cancer is a major cause of death and one of the most challenging types of cancer which responds poorly to conventional chemotherapy and has limited therapeutic options. The scenario highlights the urgent need for the development of newer multi-targeting anticancer drugs for pancreatic cancers with higher potency, selectivity and safety profiles. The proposed research was focused on revealing the anticancer potential and mechanistic involvement of naturally occurring sesquiterpenoid nootkatone against pancreatic cancer through an integrative in silico approach. Network pharmacology and systems biology approaches were applied to identify common therapeutic targets for nootkatone that were pathophysiologically associated with the progression of pancreatic cancer. Protein-protein interaction (PPI), Gene Ontology (GO), and KEGG enrichment analyses were executed to validate the target's involvement in the pathophysiology of pancreatic cancer. Molecular docking and dynamics simulations were performed to reveal the binding potential and interactions of the nootkatone with the shortlisted anticancer targets, followed by density functional theory (DFT) analysis, ADMET prediction, and clinical relevance assessment to confirm its electrochemical and physicochemical involvement. A total of 27 overlapping targets were identified with AKT1, MAPK3, IL1β, and COX-2 revealed as the four hub target genes for nootkatone by network pharmacology. Enrichment analyses confirmed the significant involvement of PD-L1/PD-1 immune checkpoint, PI3K-AKT, MAPK, and inflammatory signaling pathways (FDR < 0.05) in the progression of pancreatic cancer. Docking analyses revealed that nootkatone has binding affinity for its targets, especially for MAPK3/ERK1 (- 8.03 kcal/mol) and AKT1 (- 7.35 kcal/mol). MD simulation over 100 ns demonstrated the stable protein-ligand complexes. DFT calculations showed a HOMO-LUMO energy gap of 2.868 eV, indicating moderate chemical reactivity and stability. Nootkatone was found to exert stronger and more stable binding against all four concerned anticancer targets with impressive electrochemical properties. ADMET predictions suggested favourable drug-likeness and Pharmacokinetics. Nootkatone can be a potential multi-targeting agent with anticancer and immunomodulatory properties by modulating the PD-L1/PD-1 immune checkpoint and signalling pathways associated with pancreatic cancer progression. However, these findings are based on in silico analyses and require further validation through in vitro and in vivo experimental studies to develop new plant-based anticancer therapeutics for pancreatic cancer.