Identification of Potential Inhibitors of Cathepsin-B using Shape & Pharmacophore-based Virtual Screening, Molecular Docking and Explicit Water Thermodynamics

Lysosome has been long understood as a vital digestive organelle. Increasing reports indicate that the lysosome also plays a crucial role in the pathogenesis of a variety of neurodegenerative diseases, including Huntington's disease, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Abnormal protein degradation and deposition stimulated by lysosomal dysfunction may cause age-related neurodegeneration. Enormous efforts have been devoted to the development of effective therapeutics against Alzheimer's disease, the most debilitating neurodegenerative disease. Endopeptidase activity of the Cathepsin-B is associated with the pathological processes. Work presented here focuses on identification of new inhibitors against Cathepsin-B protein using diverse computational approaches together. The inhibitors identified were further tested for in-vitro activity using enzyme based assay method. The identified inhibitors provided interesting understanding on how the water thermodynamic properties along with hydrophobic, steric, electronic, and structural requirements contribute to cathepsin-B inhibitory activity. These water thermodynamic studies, may further be used in computer aided drug discovery pipeline to design and predict more potent derivatives of various scaffolds as cathepsin-B inhibitors.