In silico toxicity evaluation of Salubrinal and its analogues

Abstract

This paper reports on a comprehensive in silico toxicity assessment of Salubrinal and its analogues containing a cinnamic acid residue or quinoline ring using the online servers admetSAR, ADMETlab, ProTox, ADVERPred, Pred-hERG and Vienna LiverTox. Apart from rare exceptions, in all 55 studied structures, mild or practical absence of acute toxicity was predicted for rats (III or IV toxicity class). Cardiotoxic, hepatotoxic and immunotoxic effects were predicted for Salubrinal and its analogues. We constructed models of the main predicted anti-targets hERG, BSEP, MRP3, MRP4 and AhR using the principle of homologous modeling. Molecular docking studies were carried out with the obtained models. We carried out molecular docking for all targets using AutoDock Vina, implemented in the PyRx 0.8 software package. According to the results of molecular docking, the compounds analyzed are potential moderate or weak hERG blockers. Induction of cholestasis and, as a consequence, liver damage by these drugs, directly related to inhibition of BSEP, MRP3 and MRP4, most likely will not be observed. Interaction with AhR for the studied compounds is impossible for steric reasons and, as a consequence, toxic effects on the immune and other organ systems associated with the activation of the AhR signaling pathway are excluded.