Insights into molecular docking and dynamics to reveal therapeutic potential of natural compounds against P53 protein.

P53 is eminent tumour suppressor protein that plays a prominent role in cell cycle arrest, DNA repair, senescence, differentiation and initiation of apoptosis. P53 is an attractive drug target and the high toxicity of some cancer chemotherapy drugs increase the demand for new anti-cancer drugs from natural products. In this current scenario, identification of promising anticancer compounds from natural sources by repurposing approach is still relevant for the early prevention and effective management of cancer. In present study, we docked natural compounds like podophyllotoxin, quercetin and rutin along standard drugs (MG-132 and Bay 61-3606) against p53 protein. ADME/T analysis predicted toxicity of phytochemicals and drugs. In silico docking analysis of podophyllotoxin, quercetin and rutin gave HDOCK docking scores of -187.87, -148. 97 and -143.85, whereas control drugs MG-132 and Bay 61-3606 showed docking scores of -159.59 and -140.71 against p53 respectively. AutoDock analysis of rutin and MG-132 showed highest binding affinity scores of -7.3 and -6.8 kcal/mol against p53. Molecular dynamic simulation for p53 protein displayed stable conformation and convergence. In this study, P53-rutin complex showed free binding energy score of 11.84 kcal/mol and P53-MG-132 complex reported free energy score of 16.3 kcal/mol. Protein contacts atlas gives non-covalent contacts framework by exploring interfaces of individual subunits and protein-ligand interactions. STRING tool predicts physical and functional interactions between proteins. The results of this study revealed that rutin and MG-132 could be promising inhibitors against targeted p53 protein and this could prove detrimental for molecular therapeutics and drug-designing strategies.Communicated by Ramaswamy H. Sarma.

CYP1A2*1F Gene Variant, Alkaline Salt Tea Intake and Risk of Esophageal Squamous Cell Carcinoma.

Unlike many other cancers, the relationship of CYP1A2*1F (rs762551) polymorphism with esophageal squamous cell carcinoma (ESCC) risk has not been assessed so far. To evaluate its association with ESCC, we conducted a case control study in Kashmir, India, a high risk region. We recruited 404 histopathologically confirmed ESCC cases and 404 controls, individually matched for sex, age and residence to the respective cases. Information was obtained on dietary, lifestyle and environmental factors in face to face interviews using a structured questionnaire from each subject. Genotypes were analyzed by polymerase chain reaction, restriction fragment length polymorphism and sequencing randomly selected samples. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). We found that mutant genotype (AA) of CYP1A2*1F polymorphism was associated with ESCC risk (OR = 3.11; 95% CI: 1.72-5.36). A very strong ESCC risk was observed in subjects who drank >1250 ml of salt tea daily and harbored mutant genotype of CYP1A2*1F (OR = 14.51; 95% CI: 5.33-39.47). The study indicates that CYP1A2*1F polymorphism is associated with ESCC risk and the risk is modified in salt drinkers. However, more replicative and mechanistic studies are needed to substantiate the findings.

Salt tea consumption and esophageal cancer: a possible role of alkaline beverages in esophageal carcinogenesis.

Salt tea is the most commonly used beverage in Kashmir, India, where esophageal squamous cell carcinoma (ESCC) is the most common cancer. Salt tea is brewed in a unique way in Kashmir, usually with addition of sodium bicarbonate, which makes salt tea alkaline. As little information about the association between salt tea drinking and ESCC was available, we conducted a large-scale case-control study to investigate this association in Kashmir. We recruited 703 histologically confirmed cases of ESCC and 1664 controls individually matched to cases for age, sex, and district of residence. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). Participants who consumed >1,250 ml day(-1) showed an increased risk of ESCC (OR = 2.60, 95% CIs = 1.68-4.02). Samovar (a special vessel for the beverage preparation) users (OR = 1.77, 95% CIs 1.25-2.50) and those who ate cereal paste with salt tea (OR = 2.14, 95% CIs = 1.55-2.94) or added bicarbonate sodium to salt tea (OR = 2.12, 95% CIs = 1.33-3.39) were at higher risk of ESCC than others. When analysis was limited to alkaline tea drinkers only, those who both consumed cereal paste with salt tea and used samovar vessel were at the highest risk (OR = 4.58, 95% CIs = 2.04-10.28). This study shows significant associations of salt tea drinking and some related habits with ESCC risk.