Equilibrium between tri- and tetra-coordinate chalcogenuranes is critical for cysteine protease inhibition.

There have been significant advances in the biological use of hypervalent selenium and tellurium compounds as cysteine protease inhibitors. However, the full understanding of their reaction mechanisms for and cysteine proteases inhibition is still elusive. Kinetic studies suggest an irreversible inhibition mechanism, which was explained by forming a covalent bond between the enzyme sulfhydryl group and the chalcogen atom at its hypervalent state (+4). In this work, we performed a theoretical investigation using density functional theory to propose the active inhibitor form in an aqueous solution. To this end, we investigated chloride ligand exchange reactions by oxygen and sulfur nucleophiles on hypervalent selenium and tellurium compounds. All tetra- and tri-coordinated chalcogen compounds and distinct protonation states of the nucleophiles were considered, totaling 34 unique species, 7 nucleophiles, and 155 free energies reactions. We discovered that chloride is easily replaced by a nonprotonated nucleophile (SH- or OH- ) in R2 SeCl2 . We also found that tri-coordinate species are more stable than their tetra-coordinate counterparts, with selenoxide (R2 SeO) protonation being strongly exergonic in acid pH. The thermodynamic and kinetic results suggest that the protonated selenoxide (R2 SeOH+ ) is the most probable active chemical species in biological media. The computed energetic profiles paint a possible picture for selenuranes activity, with successive exergonic steps leading to a covalent inhibition of thiol-dependent enzymes, like cysteine proteases. A second pathway has also been uncovered, with a direct reaction to chalcogenonium cation (R2 SeCl+ ) as the inhibition step. Tellurium compounds showed similar trends but formed telluroxide in a pH-independent fashion.