Molecular dynamic simulation (MDS) and in vitro cathepsin-B inhibitory activity of decrusin angelate, ibuprofen, and thymol

Abstract

Attenuation of cathepsin B (CATB) proteolytic activity and/or inhibition serves as a potential therapeutic target in cancer metastasis. Herein, we determined the specificity of FDA approved potential anti-cancer natural flavonoid decursinol angelate (DA), thymol (TH) and a propionic acid derivative ibuprofen (IB), for the inactivation of CATB. We used enzymatic assay, computational and in vitro methods for the identification of the best candidate. Out of these we found DA can inhibit CATB with lowest IC₅₀ measured after one hour of incubation using Z-Phe-Arg-4MβNA (BANA) as a substrate. Docking analysis suggested favorable interaction of DA with the catalytic site residues (GLN23, CYS26, HIS110, HIS111) of CATB (PDB Id: 1HUC) were responsible for the inhibition of its proteolytic activity. Additionally, in vitro quantification with human colorectal carcinoma (HCT 116) revealed, DA rapidly inactivates CATB as compared with commercial synthetic inhibitor CA074 with no cellular toxicity towards normal colon cells (CCD 841).

Graphical Abstract

Keywords:

• Cathepsin B
• colon cancer
• decursinol angelate
• enzymatic assay
• molecular docking
• molecular dynamics

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The present research was supported by grants from the National Research Fund (NRF 2019R1A2B5B01070543), South Korea.