Computational study on the inhibition mechanism of cruzain by nitrile-containing molecules

Cysteine proteases from parasites as well as from mammals are promising drug targets for parasitic infections and systemic human diseases, respectively. Many reversible and irreversible inhibitors of this very large class of proteins have been designed. Among others, molecules with a nitrile moiety, which is a group that is susceptible to a nucleophilic attack by the enzyme, have been identified as good inhibitors. Although it is known that the nitrile group binds covalently to Cys25, there are no reports about the energetics involved in the mechanism of this process. Herein, density functional theory and quantum semi-empirical calculations were conducted in order to study the molecular recognition of cysteine proteases by nitrile-containing molecules. Results reported in this paper suggest an interaction that starts with a nucleophilic attack from the Cys25 to the inhibitor followed by a proton transfer from His162. Only one transition state was detected; however, we found the existence of an energy plateau in the potential energy surface. Based on the proposed mechanism, some structural features that could improve the biological activity of nitrile-containing molecules toward cysteine proteases are discussed.

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► Cysteine proteases, involved in many diseases, represent promising drug targets.
► We model the covalent inhibition of cysteine proteases by purine-carbonitriles.
► Inhibition occurs via a concerted mechanism that starts with a nucleophilic attack.
► Reversibility could be managed by modulating the proton transfer from the His162.
► Increased electrophilicity in the nitrile carbon might facilitate the inhibition.