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

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 IC 50 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 IC 50 values for proteasome inhibition. Furthermore, the Sn atom in TBT and TPT was found susceptible to form a coordinate bond with Thr 1 O  of the 5 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.docking, organotin, proteasome, chymotrypsin-like activity

Proteasome as a Molecular Target of Microcystin-LR

“…Autodock 4.0 software is a free docking tool designed to predict the manner by which small molecules bind to a receptor of a known 3D structure. This tool has been successfully utilized in docking analyses of several proteasome inhibitors [ 36 , 37 ]. In the present study, Autodock 4.0 software was used to investigate the interaction of MC-LR with the β1, β5, and β2 subunits of the 20S proteasome.…”

“…The binding of MC-LR to proteasome subunits was analyzed in silico using AutoDock 4.0 software (from the Scripps Research Institute, La Jolla, CA, USA), similar as described previously [ 36 ]. We initially refined the MC-LR molecular by performing an optimized geometry calculation of the saved Protein Data Bank (PDB) files; this procedure was conducted using the conversion filters in CAChe software V6.1.10 (Fujitsu, Fairfield, NJ, USA).…”

“…The docking space was limited to a 40 × 40 × 40 Å box centered on the catalytic N ­terminal threonine prepared as an energy­scoring grid. AutoDock outputs were visualized and analyzed with PyMOL software (Schrödinger, New York, NY, USA) [ 36 ].…”

Computational Approaches for the Discovery of Human Proteasome Inhibitors: An Overview

“…Also in 2010, Shi et al [132] carried out docking simulations in order to identify the interaction mode of butyltin and phenyltin compounds (organotins) with proteasome β5 subunit (CT-L). Docking calculations were performed with AutoDock software by using eukaryotic yeast 20S proteasome.…”

“…Computational and biological studies demonstrated different interactions with the β5 subunit. The authors concluded that tributyltin and triphenyltin were irreversible inhibitors, while organotins with one or two butyl substitutes or with one or two phenyl substitutes were reversible inhibitors [132].…”