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Molecular modeling for the interaction between proteasome beta 5 subunit and organotin compounds
Authors:GuoQing Shi  Qing Sun  HuanJie Yang  QingPing Dou  QianMin Deng  HaiOu Wang  GuangRong Zhong
Institution:1. Department of Biological Science and Technology, School of Applied Science, University of Science and Technology Beijing, Beijing, 100083, China
2. The Prevention Program, Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pathology and Pharmacology, School of Medicine, Wayne State University, Detroit, Michigan, MI, 48201, USA
Abstract: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 Oγ 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.
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