Cathepsin B is a cysteine protease that belongs to the papain superfamily. Malfunctions related to
cathepsin B can lead to inflammation and cancer. Via an integrated in silico approach, this study is aimed to
identify novel Michael acceptors-type compounds that can irreversibly inhibit cathepsin B enzyme via
covalent bond formation with the active site cysteine residue. Here, we report the first account of covalent
docking approach incorporated into a hybrid ligand/structure-based virtual screening to estimate the binding
affinities of various compounds from chemical databases against the cathepsin B protein. For validation,
compounds with experimentally determined anti-cathepsin B activity from PubChem bioassay database
were also screened and covalently docked to the enzyme target. Interestingly, four novel compounds exhibited better covalent
binding affinity when compared against the experimentally determined prototypes. Molecular dynamics simulations were
performed to ensure the stability of the docked complexes and to allow further analysis on the MD average structures. Perresidue
interaction decomposition analysis was carried out to provide deeper insight into the interaction themes of discovered hits
with the active site residues. It is found that polar and hydrophobic interactions contributed the most towards drug binding.
The hybrid computational methods applied in this study should serve as a powerful tool in the drug design and
Keywords: Cathepsin B, covalent docking, Michael acceptors, molecular dynamics, virtual screening.
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