METHODS: Kinetic studies were used to investigate the interactions between the three GSTs and each of glutathione, 1-chloro-2,4-dinitrobenzene, cibacron blue, ethacrynic acid, S-hexyl glutathione, hemin and protoporphyrin IX. Since hemin displacement is intended for PfGST inhibitors, the interactions between hemin and other ligands at PfGST binding sites were studied kinetically. Computationally determined binding modes and energies were interlinked with the kinetic results to resolve enzymes-ligands interaction models at atomic level.
RESULTS: The results showed that hemin and cibacron blue have different binding modes in the three GSTs. Hemin has two binding sites (A and B) with two binding modes at site-A depending on presence of GSH. None of the ligands were able to compete hemin binding to PfGST except ethacrynic acid. Besides bind differently in GSTs, the isolated anthraquinone moiety of cibacron blue is not maintaining sufficient interactions with GSTs to be used as a lead. Similarly, the ethacrynic acid uses water bridges to mediate interactions with GSTs and at least the conjugated form of EA is the true hemin inhibitor, thus EA may not be a suitable lead.
CONCLUSIONS: Glutathione analogues with bulky substitution at thiol of cysteine moiety or at γ-amino group of γ-glutamine moiety may be the most suitable to provide GST inhibitors with hemin competition.
METHODS: Cigarette and alcohol use was assessed in a large cross-sectional national sample aged 50 years and above from the Irish Longitudinal Study on Ageing (TILDA) (n = 6,576). The Brief Ageing Perceptions Questionnaire (BAPQ) assessed individual's views of their own ageing across five domains. Study hypothesis that stronger beliefs on each of the BAPQ domains would be related to drinking and smoking was examined using multinomial logit models (MNLM). Regression parameter estimates for all variables were estimated relative risk ratios (RRR).
RESULTS: More women were non-drinkers (30 % vs. 20 %) and men displayed significantly higher alcohol use patterns. One in five older Irish adults was a current smoker (16.8 % of women, 17 % of men), and smoking and harmful drinking were strongly associated (P