In silico design of 2,2'-dihydroxybenzophenones and xanthone analogues to inhibit human glutathione transferase's (hGSTs) involvement in Multiple Drug Resistance.

Abstract

Glutathione S-transferases catalyze the conjugation of glutathione (GSH) to a variety of hydrophobic substrates, rendering them hydrophilic and facilitating their metabolic processing and secretion from the cell. GSTs are involved in major detoxification mechanisms of the cell from several xenobiotics and drugs. On the other hand, on the basis of the same detoxification mechanisms, cancer cells may acquire resistance by overexpressing GST activities, thus hampering the effectiveness of certain chemotherapeutic drugs and leading to chemotherapeutic resistant tumor cells. Several synthetic drugs and prodrugs exhibiting inhibition potency against GSTs have been proposed as strategies to overcoming multiple drug resistance (MDR) attributed to GST overexpression. In the pursuit of identifying new lead compounds as inhibitors against hGSTs involved in MDR we have used Structure Based Ligand Design techniques to generate in silico xanthone and benzophenone derivatives and performed extensive molecular docking and binding evaluation on the structure of hGSTA1-1.