Reaction mechanism of cysteine proteases model compound HSH with diketone inhibitor PhCOCOCH3−nXn, (X = F,Cl, n = 0, 1, 2)

Caspases are a family of cysteine proteases, which play a crucial role in apoptosis and inflammation. The reaction mechanisms involving the cysteine proteases model compound HSH with diketone (PhCOCOCH_3‐nX_n, (X = F, Cl, n = 0, 1, 2) substrate have been studied using B3LYP/6‐311+G* level of density functional theory method. The harmonic vibrational frequencies were calculated at the same level of theory used for the characterization of stationary points and zero‐point vibrational energy corrections. The condensed Fukui functions have been calculated to find the favorable reactive site for the electrophilic (f), nucleophilic (f), and radical (f) attacks in the reactants. The transition states were connected with reactants, intermediate, and products, and the minimum energy paths have been confirmed through intrinsic reaction coordinate calculation. The potential energy barrier between each step of the reactions has been calculated to find the most favorable reaction path. The binding nature of cysteine model compound with diketone substrate has been studied through the interaction energies, bond lengths, electron density, natural bond orbital, and atoms in molecules theory analysis. © 2009 Wiley Periodicals, Inc. Int J Quantum Chem, 2010