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

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

Plant Glutathione Transferases: Structure, Antioxidant Catalytic Function and in planta Protective Role in Biotic and Abiotic Stress

Plant cytosolic glutathione transferases (GSTs) belong to an ancient enzyme superfamily with multiple and diverse functions which are important in counteracting biotic and abiotic stress. GSTs catalyze the conjugation of xenobiotics and endogenous electrophilic compounds with glutathione (GSH), leading to their detoxification. GSTs not only catalyze detoxification reactions but they are also involved in GSH-dependent isomerization reactions, in GSH-dependent reduction of organic hydroperoxides, biosynthesis of secondary metabolites, and exhibit thioltransferase and dehydroascorbate reductase activity. The applications of ‘omics’ technologies have allowed the classification of GSTs and the study of their evolution and sequence diversity, while enzymology has provided powerful insights into their catalytic role. This review focuses on plant GSTs, and attempts to give an overview of the new insights into their catalytic function and biological role in biotic and abiotic stress tolerance mechanisms in plants

Drivers’ Reaction Time and Mental Workload: A Driving Simulation Study

Drivers play a significant role in causing serious accidents, which underscores the need for further investigating the human element in order to improve road safety. Given the predominance of the information processing approach in driver’s behavior research field, an important psychological construct, Mental Workload (MWL), has been introduced to study the behavior of drivers. The objective of this paper is to investigate the impact of increased MWL on driver behavior and specifically the changes in driver’s Reaction Time (RT) under increased MWL. The experiment conducted in the driving simulator of the Hellenic Institute of Transport which is part of the Centre for Research and Technology Hellas, with the participation of 56 subjects from all age groups. For the simulation of the increased MWL conditions during driving, a secondary task was employed. To this end, the MIT AgeLab Delayed Digit Recall Task in the 1-back version was adapted for the needs of the present research. The driving scenario included 4 unexpected events, which further increase driver’s MWL. Driving performance was observed and relative parameters were measured as RT on the unexpected events, accidents occurred, and maneuvers performed. Appropriate statistical analysis was performed to examine the difference in the drivers’ RT in the unexpected events. Results demonstrated that higher MWL increased drivers’ RT in the majority of the participants. Furthermore, results also indicated a number of participants that probably employed adaptive control behaviors to counterbalance the increased MWL. Overall, variance on MWL proved to play an important role on driver performance, and thus further research on its consequences on driving performance, and the factors that influence its variance during driving, is imperative

Inhibition Analysis and High-Resolution Crystal Structure of <i>Mus musculus</i> Glutathione Transferase P1-1

Multidrug resistance is a significant barrier that makes anticancer therapies less effective. Glutathione transferases (GSTs) are involved in multidrug resistance mechanisms and play a significant part in the metabolism of alkylating anticancer drugs. The purpose of this study was to screen and select a lead compound with high inhibitory potency against the isoenzyme GSTP1-1 from Mus musculus (MmGSTP1-1). The lead compound was selected following the screening of a library of currently approved and registered pesticides that belong to different chemical classes. The results showed that the fungicide iprodione [3-(3,5-dichlorophenyl)-2,4-dioxo-N-propan-2-ylimidazolidine-1-carboxamide] exhibited the highest inhibition potency (ΙC50 = 11.3 ± 0.5 μΜ) towards MmGSTP1-1. Kinetics analysis revealed that iprodione functions as a mixed-type inhibitor towards glutathione (GSH) and non-competitive inhibitor towards 1-chloro-2,4-dinitrobenzene (CDNB). X-ray crystallography was used to determine the crystal structure of MmGSTP1-1 at 1.28 Å resolution as a complex with S-(p-nitrobenzyl)glutathione (Nb-GSH). The crystal structure was used to map the ligand-binding site of MmGSTP1-1 and to provide structural data of the interaction of the enzyme with iprodione using molecular docking. The results of this study shed light on the inhibition mechanism of MmGSTP1-1 and provide a new compound as a potential lead structure for future drug/inhibitor development