Abstract
Cathepsin-D (CATD) inhibitors' design and development drawn interest due to their potential therapeutic applications in managing different cancer types, including lung cancer. This study investigated myricitrin, a flavonol-3-O-rhamnoside, for its binding affinity to CATD. Molecular docking experiments revealed a strong binding affinity (-7.8kcal/mol). Molecular dynamics (MD) simulation confirmed the complex's stability, while enzyme activity studies showed inhibitory concentration (IC50) of 35.14±6.08μM (in cell-free) and 16.00±3.48μM (in cell-based) test systems. Expression analysis indicated downregulation of CATD with a fold change of 1.35. Myricitrin demonstrated antiproliferative effects on NCIH-520cells [IC50: 64.11μM in Sulphorhodamine B (SRB), 24.44μM in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)], but did not affect healthy CHANG cells. It also prolonged the G2/M phase (at 10μM: 1.19-fold; at 100μM: 1.13-fold) and increased sub-diploid population by 1.35-fold. Based on the analysis done using SwissADME program, it is predicted that myricitrin is not a cytochrome p450s (CYPs) inhibitor, followed the rule of Ghose and found not permeable to the blood-brain barrier (BBB) which suggests it as a safe molecule. In summary, the experimental findings may establish the foundation for myricitrin and its analogues to be used therapeutically in CATD-mediated lung cancer prevention.
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