IN-SILICO EVALUATION OF CHAMAZULENE AS A POTENTIAL INHIBITOR OF KRÜPPEL-LIKE FACTOR 5 IN PANCREATIC CANCER: MOLECULAR DOCKING, PHARMACOKINETIC AND TOXICITY PROFILING AND MOLECULAR DYNAMICS SIMULATION

Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive and treatment-resistant cancers, often driven by aberrant KRAS signalling. Kruppel-like factor 5 (KLF5), a downstream transcription factor in this pathway, has emerged as a potential therapeutic target. Chamazulene, a bioactive sesquiterpene derived from Matricaria chamomilla, known for its anti-inflammatory and antioxidant properties, but its anticancer potential remains unexplored. Objective: To evaluate the drug-likeness, toxicity, and KLF5-targeting potential of Chamazulene using an integrated in-silico approach. Methods: Chamazulene’s physicochemical and pharmacokinetic properties were assessed via SwissADME and PreADMET tools. Toxicity predictions were obtained using the GUSAR server. Molecular docking against homology-modelled KLF5 was performed using AutoDock Vina, and binding interactions were visualized. The top-scoring complex was further analyzed through 100-nanosecond molecular dynamics simulation using Desmond to assess structural stability under physiological conditions. Results: Chamazulene demonstrated favorable drug-likeness, high gastrointestinal absorption, BBB permeability, and a bioavailability score of 0.55. It showed no predicted hepatotoxicity or mutagenicity and had a high lethal dose (LD₅₀) value (>5000 mg/kg), although carcinogenic potential was flagged. Docking revealed a stable interaction with KLF5 (-5.9 kcal/mol), with hydrogen bonding to Tyr272 and favorable hydrophobic contacts. Molecular dynamics (MD) simulations confirmed complex stability, with RMSD values below 2 Å and preserved secondary structure. Conclusion: Chamazulene shows strong potential as a KLF5 inhibitor, with promising pharmacokinetic and structural interaction profiles. Further in-vitro and in-vivo validation is essential to confirm its therapeutic role in pancreatic cancer.