An Insilico Elucidation of Inhibition of Cathepsin D by 2, 4, 5-triaryl Imidazole Derivatives

Cathepsin D (EC 3.4.23.5), a lysosomal protease, is strategically very important aspartic protease in transferring different signals to the different cells and to the same cell at different state of growth. Being a mitogen and regulator for the several precursors of growth factors, it’s over expression leads to metastasis. It may also internalize in cancer cells by exploring its mitogenic property. The inhibition of this particular aspartic protease may be the one of the strategy to control metastasis of the breast cancer. There have been several inhibitors proposed to regulate the cathepsin D but the quest to find the best is still unexplored. In this study we propose the imidazole derivatives (a-e), which have been designed and synthesized in our laboratory, as potent cathepsin D inhibitors which have been shown to inhibit HIV-1 PR and pepsin in wet lab studies. Docking study of API (Aspartic protease inhibitors) with Cathepsin D was performed in order to find specific binding model using AutoDock 4.0 based on x-ray structure of Cathepsin D (PDB:1LYB). Basically, blind docking was conducted to predict the most preferred binding pockets of ligands in the protein molecule. Results were matched with original active site of Cathepsin D. From the docking results it was observed that compound b (2-(4-methoxyphenyl)-4,5 dip-tolyl-1H-imidazole) showed strong interaction with cathepsin D in terms of better binding energy (-11.21Kcal/mol) and inhibition constant (3.2 nM). Compound a (2-(4,5 dip-tolyl-1H-imidazole-2-yl) Phenol), c (2-Phenyl-4,5-dip-toly-1H-imidazole) d (4-(4,5-dip-tolyl-1H-imidazole-2-yl)-2methoxyphenol) and e (2-(4-methoxyphenyl)-4,5-diphenyl-1H-imidazole) appeared to be very potent inhibitor of cathepsin D catalytic activity with inhibition constant (Ki) values of 6.1, 4.9, 16.5 and 8.7 nM respectively. The results suggest that 2,4,5-triaryl imidazole derivatives might be considered as promising chemopreventive agents.