Mechanistic insights into the inhibition mechanism of cysteine cathepsins by chalcone-based inhibitors—a QM cluster model approach

Abstract

Cathepsins are the most abundant cysteine proteases involved in many physiological processes. The imbalance between the natural cysteine protease inhibitors and cathepsins leads to many pathological conditions such as cancer, osteoporosis, and osteoarthritis. Thus, cysteine cathepsins have turn out to be an attractive therapeutic target for the development of new inhibitors. In this paper, the computational study of the inhibition mechanism of cysteine protease by chalcone-based inhibitors has been carried out by means of quantum chemical calculations by employing DFT method. The present study exposes how the processes of activation of the reactive centers of the chalcone derivatives and the nucleophilic attack by the cysteine residue at the electrophilic reactive site of the chalcone take place in the catalytic active site. The obtained results reveal that the inhibition reaction proceeds in a stepwise manner and the attack of the cysteine residue will be either at carbonyl carbon C32 (pathway 1) or β-carbon C33 (pathway 2). The low positive activation (5.61 and 4.58 kcal/mol) and reaction (1.60 and 9.70 kcal/mol) energies corresponding to both the pathways along with the positive ∇2ρ(r) values for C32/33–S6 bonds imply that the overall reaction is endothermic and the nature of inhibitor is reversible covalent.