Molecular modeling for the interaction between proteasome beta 5 subunit and organotin compounds

It has been reported that organotins can inhibit the proteasomal chymotrypsin-like activity and induce cell death, but the interaction mode of organotins with proteasome has not been well defined. In this study, the IC₅₀ of butyltins and phenyltins against the proteasomal activity and the nature of their inhibition were investigated. It was found that both mono- and di-organotins were weak, reversible inhibitors against the proteasome, while tributyltin and triphenyltin were potent, irreversible proteasome inhibitors. In silico studies using the reversible organotin proteasome inhibitors demonstrated a tight correlation of the estimated proteasomal inhibition constants (Ki) with the experimental IC₅₀ values for proteasome inhibition. Furthermore, the Sn atom in TBT and TPT was found susceptible to form a coordinate bond with Thr 1 O^γ of the β5 subunit, which may account for the irreversible proteasome inhibition. The computational docking approach well predicted the inhibition nature of organotins toward the proteasomal chymotrypsin-like activity. This predictive model might aid in understanding the cytotoxic behavior of similar organometallic compounds.