In silico docking of methyl isocyanate (MIC) and its hydrolytic product (1, 3-dimethylurea) shows significant interaction with DNA Methyltransferase 1 suggests cancer risk in Bhopal-Gas-Tragedy survivors

Khan, Inbesat; Senthilkumar, Chinnu Sugavanam; Upadhyay, Nisha; Singh, Hemant Kumar; Sachdeva, Meenu; Jatawa, Suresh Kumar; Tiwari, Archana

doi:10.7314/apjcp.2015.16.17.7663

Cited by 5 publications

(3 citation statements)

References 63 publications

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“…Preliminarily, the preparation was preprocessed to assign bond orders to all bonds, add hygrogens to all atoms, creat disulfide bonds within 3.2 Å, cap termini to fill up ACE (N-acetyl) and NMA (N-methyl amide) and delete all unrelated waters [28]. Hydrogen bonding network and the orientation of Asn, Gln and His residues were optimized with H-bond assignment section [29].…”

Section: Methodsmentioning

confidence: 99%

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Design, sythesis and evaluation of a series of 3- or 4-alkoxy substituted phenoxy derivatives as PPARs agonists

et al. 2017

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Peroxisome proliferators-activated receptors (PPARα, γ and δ) are potentially effective targets for Type 2 diabetes mellitus therapy. The severe effects of known glitazones and the successfully approved agents (saroglitazar and lobeglitazone) motivated us to study novelly potent PPARs drugs with improved safety profile. In this work, we received 15 carboxylic acids based on the combination principle to integrate the polar head of bezafibrate with the hydrophobic tail of pioglitazone. Another 12 tetrazoles based on the bioisosterism principle were obtained accordingly. Furthermore, in vitro PPARs transactivation assays on these 3- or 4-alkoxy substituted phenoxy derivatives afforded six compounds. Interactions and binding stability from the docking analysis and 20 ns molecular dynamic simulations confirmed the representative compounds to be suitable and plausible for PPARs pockets. The above-mentioned results demonstrated that the compounds may be used as reference for further optimization for enhanced PPARs activities and wide safety range.

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Section: Methodsmentioning

confidence: 99%

“…Ligand preparation was calculated with the LigPrep panel (Schrödinger, LLC, New York, 2015) to produce the corresponding low-energy 3D structures [32–34], which generated possible ionization states (at target PH: 7.0+/−2.0) [31], stereoisomers, tautomers and ring conformations [28]. …”

Section: Methodsmentioning

confidence: 99%

Design, sythesis and evaluation of a series of 3- or 4-alkoxy substituted phenoxy derivatives as PPARs agonists

et al. 2017

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“…Therefore, carcinogenicity tests are now applied to detect carcinogenic potential of pesticides before allowing them to be marketed. These carcinogenicity testing is conducted by the Environmental Protection Agency (US-EPA), and it is a long-term (around two years) rodent bioassay using two species of both sexes, and according to a new list of chemicals evaluated for carcinogenic potential by EPA's pesticide program published in 2010, more than 70 pesticides have been classified as a probable or possible carcinogen [12]. This classification has been accomplished based on the information extracted from animal genotoxicity and mutagenicitybased studies, and there is a need for human-based clinical trials to address these issues.…”

Section: Introductionmentioning

confidence: 99%

Pesticides Exposure in Relevance to Cancer Risk

Mi¹

2017

OAJAR

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Pesticides are widely used throughout the world because of their benefits to maintain high agricultural products quality and quantity. There is growing epidemiological evidence that exposure of humans to pesticides correlate with an increased incidence of cancer. Agricultural health studies often established a positive correlation between occupational exposure to pesticides and different types of cancer; however data on non-occupational exposures are scarce to draw any conclusion. The frequency of cancer diagnosis has increased dramatically among adults population, and there are no studies addressing the impact of pesticides or their residues on cancer development among high risk groups of adults' population. Cancer is the second leading cause of chronic diseases-related death among adults, yet there is no enough information to link pesticides exposure and cancer incidence. The biological link between pesticides use and increasing cancer incidence needs to be addressed, in particular the biochemical and epigenetic modifications that might be associated with continuous pesticides exposure. Lack of evidence in this regard has promoted us to write this mini-review as an attempt to evaluate the mechanisms by which pesticides develop cancer, and we hypothesized that long-term exposure to pesticides induce cellular oxidative stress, epigenetic modifications, and alterations of DNA methylation in multiple human organ systems leading to cancer development among high risk groups.

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Identification of dual ligands targeting angiotensin II type 1 receptor and peroxisome proliferator-activated receptor-γ by core hopping of telmisartan

Zhang

Liu

Wang

et al. 2016

Journal of Biomolecular Structure and Dynamics

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It has been reported previously that some angiotensin II receptor blockers not only antagonize angiotensin II type 1 receptor (ATR), but also exert stimulation in peroxisome proliferator-activated receptor γ (PPARγ) partial activation, among which telmisartan displays the best. Telmisartan has been tested as a bifunctional ligand with antihypertensive and hypoglycemic activity. Aiming at more potent leads with selective ATR antagonism and PPARγ partial agonism, the three parts of telmisartan including the distal benzimidazole ring, the biphenyl moiety, and the carboxylic acid group experienced modification by core hopping method in our study. The central benzimidazole ring, however, remained intact considering its great affinity toward ATR and PPARγ. We utilized computational techniques for the sake of details on the binding interactions and conformational stability. Standard precision docking analysis and absorption, distribution, metabolism, excretion, and toxicity prediction received 10 molecules with higher Glide scores, similar interactions, and improved pharmacokinetic profiles compared to telmisartan. Comp#91 with highest scores for ATR (-11.92 kcal/mol) and PPARγ (-13.88 kcal/mol) exhibited excellent binding modes and pharmacokinetic parameters. Molecular dynamics trajectories on best docking pose of comp#91 confirmed the docking results and verified the conformational stability with both receptors throughout the course of 20-ns simulations. Thus, comp#91 could be identified as a promising lead in the development of dual ATR antagonist and PPARγ partial agonist against hypertension and type 2 diabetes.

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In silico docking of methyl isocyanate (MIC) and its hydrolytic product (1, 3-dimethylurea) shows significant interaction with DNA Methyltransferase 1 suggests cancer risk in Bhopal-Gas-Tragedy survivors

Cited by 5 publications

References 63 publications

Design, sythesis and evaluation of a series of 3- or 4-alkoxy substituted phenoxy derivatives as PPARs agonists

Design, sythesis and evaluation of a series of 3- or 4-alkoxy substituted phenoxy derivatives as PPARs agonists

Pesticides Exposure in Relevance to Cancer Risk

Identification of dual ligands targeting angiotensin II type 1 receptor and peroxisome proliferator-activated receptor-γ by core hopping of telmisartan

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