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1.
Ecotoxicology ; 23(6): 967-77, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24777664

ABSTRACT

Harike is a wetland of international importance under the Ramsar Convention. The present study entails the investigation of mutagenic, genotoxic and cytotoxic effect of surface water samples collected from five different areas of the Harike wetland by using the histidine reversion point mutation assay in Salmonella typhimurium (TA98 and TA100) strain with or without S9, bioluminescence mutagenicity assay using Vibrio harveyi (A16) strain, plasmid-nicking assay using pBR322 and 3(4,5-dimethyl-thiazol-2-yl)2,5-diphenyl-tetrazolium bromide assay as well as confocal imaging studies using Chinese hamster ovarian cell line, respectively. It was observed that although, the water sample of all the areas of wetland demonstrated mutagenic, genotoxic as well as cytotoxic activity, the effect was quite significant with the water samples from River Satluj and Khatan area (i.e. reservoir mainly contains Satluj water). The metal analysis of water samples was also conducted with atomic absorption spectrophotometer. The mutagenicity, genotoxicity and cytotoxicity of water samples emerged to be correlated with metal concentration. The source of toxic components seems to be associated with various industrial effluents and agricultural run-off. The results of the present study carry great importance in documenting the water quality monitoring data of the wetland.


Subject(s)
Environmental Monitoring , Wetlands , Animals , CHO Cells , Cricetinae , Cricetulus , Fresh Water/chemistry , India , Metals, Heavy/analysis , Mutagenicity Tests , Salmonella typhimurium/drug effects , Water Pollutants, Chemical/analysis
2.
Environ Sci Pollut Res Int ; 21(3): 1599-1613, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24170504

ABSTRACT

Oxidative stress has been a major predicament of present day living. It has been the product of imbalance between the processes involved in free radical generation and their neutralization by enzymatic and non-enzymatic defence mechanisms. The oxidative stress has been contributed by numerous factors including heavy metals, organic compound-rich industrial effluents, air pollutants and changing lifestyle pattern focussing mainly on alcohol consumption, dietary habits, sun exposure, nuclear emissions, etc. The most common outcome of oxidative stress is the increased damage of lipid, DNA and proteins that resulted in the development of different pathologies. Among these pathologies, cancer is the most devastating and linked to multiple mutations arising due to oxidative DNA and protein damage that ultimately affect the integrity of the genome. The chemopreventive agents particularly nutraceuticals are found to be effective in reducing cancer incidences as these components have immense antioxidative, antimutagenic and antiproliferative potentials and are an important part of our dietary components. These secondary metabolites, due to their unique chemical structure, facilitate cell-to-cell communication, repair DNA damage by the downregulation of transcription factors and inhibit the activity of protein kinases and cytochrome P450-dependent mixed function oxidases. These phytochemicals, therefore, are most appropriate in combating oxidative stress-related disorders due to their tendency to exert better protective effect without having any distinct side effect.


Subject(s)
Oxidative Stress , Antioxidants/metabolism , Environmental Pollutants/toxicity , Free Radicals/metabolism , Humans , Metals, Heavy/toxicity , Oxidation-Reduction , Phytochemicals/metabolism
3.
Bioorg Med Chem Lett ; 22(13): 4296-302, 2012 Jul 01.
Article in English | MEDLINE | ID: mdl-22672799

ABSTRACT

A potent inhibitor of PI3Kδ that is ≥ 200 fold selective for the remaining three Class I PI3K isoforms and additional kinases is described. The hypothesis for selectivity is illustrated through structure activity relationships and crystal structures of compounds bound to a K802T mutant of PI3Kγ. Pharmacokinetic data in rats and mice support the use of 3 as a useful tool compound to use for in vivo studies.


Subject(s)
Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/chemistry , Tryptophan/chemistry , Animals , Binding Sites , Computer Simulation , Female , Injections, Intravenous , Liver/metabolism , Male , Mice , Mice, Inbred BALB C , Mutation , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/genetics , Protein Isoforms/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Protein Structure, Tertiary , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
4.
J Med Chem ; 55(12): 5887-900, 2012 Jun 28.
Article in English | MEDLINE | ID: mdl-22626259

ABSTRACT

PI3Kδ is a lipid kinase and a member of a larger family of enzymes, PI3K class IA(α, ß, δ) and IB (γ), which catalyze the phosphorylation of PIP2 to PIP3. PI3Kδ is mainly expressed in leukocytes, where it plays a critical, nonredundant role in B cell receptor mediated signaling and provides an attractive opportunity to treat diseases where B cell activity is essential, e.g., rheumatoid arthritis. We report the discovery of novel, potent, and selective PI3Kδ inhibitors and describe a structural hypothesis for isoform (α, ß, γ) selectivity gained from interactions in the affinity pocket. The critical component of our initial pharmacophore for isoform selectivity was strongly associated with CYP3A4 time-dependent inhibition (TDI). We describe a variety of strategies and methods for monitoring and attenuating TDI. Ultimately, a structure-based design approach was employed to identify a suitable structural replacement for further optimization.


Subject(s)
Arthritis, Rheumatoid/drug therapy , Cytochrome P-450 CYP3A Inhibitors , Drug Discovery , Enzyme Inhibitors/pharmacology , Phosphoinositide-3 Kinase Inhibitors , Arthritis, Rheumatoid/enzymology , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Benzimidazoles/therapeutic use , Cell Line , Cytochrome P-450 CYP3A , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Humans , Inhibitory Concentration 50 , Models, Molecular , Phosphatidylinositol 3-Kinases/chemistry , Protein Conformation , Substrate Specificity , Time Factors
5.
J Comput Aided Mol Des ; 18(10): 635-50, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15849994

ABSTRACT

An approach for docking covalently bound ligands in protein enzymes or receptors was implemented in MacDOCK, a similarity-driven docking program based on DOCK 4.0. This approach was tested with a small number of covalent ligand-protein structures, using both native and non-native protein structures. In all cases, MacDOCK was able to generate orientations consistent with the known covalent binding mode of these complexes, with a performance similar to that of other docking programs. This method was also applied to search for known covalent thrombin inhibitors in a medium-sized molecular database (ca. 11,000 compounds). Detection of functional groups suitable for covalent docking was carried out automatically. A significant enrichment in known active molecules in the first 5% of the database was obtained, showing that MacDOCK can be used efficiently for the virtual screening of covalently bound ligands.


Subject(s)
Computer Simulation , Enzymes/metabolism , Protein Binding/physiology , Receptors, Cell Surface/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Ligands , Software , Thrombin/antagonists & inhibitors
6.
Org Biomol Chem ; 1(23): 4235-41, 2003 Dec 07.
Article in English | MEDLINE | ID: mdl-14685325

ABSTRACT

A collection of small molecules (MW < 350 Da) was screened for binding to human factor Xa using saturation transfer difference NMR spectroscopy to detect binding. The NMR screening experiments identified four hits. Binding isotherms constructed from NMR linewidth data showed that the binding affinities of the hits were all in the 30-210 microM range. Competition binding experiments showed that three of the ligands were displaced by a known microM inhibitor of factor Xa. The success of the method for identifying new ligands and the relevance of this information to the design of new factor Xa inhibitors are discussed.


Subject(s)
Factor Xa/chemistry , Factor Xa/metabolism , Molecular Probes/chemistry , Molecular Probes/metabolism , Binding Sites , Binding, Competitive , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Factor Xa Inhibitors , Humans , Ligands , Magnetic Resonance Spectroscopy , Molecular Structure
7.
Bioorg Med Chem Lett ; 12(2): 193-6, 2002 Jan 21.
Article in English | MEDLINE | ID: mdl-11755352

ABSTRACT

A series of oxyanilinium-based AChE inhibitors have been synthesised and tested for the reversal of vecuronium-induced neuromuscular block. Several compounds, for example 2-hydroxy- and 2-methoxy-N,N-dimethyl-N-allylanilinium bromide (3 and 6) showed comparable reversal potencies to edrophonium and clean in vivo cardiovascular profiles.


Subject(s)
Acetylcholinesterase/drug effects , Allyl Compounds/pharmacology , Aniline Compounds/pharmacology , Cholinesterase Inhibitors/pharmacology , Edrophonium/antagonists & inhibitors , Neuromuscular Blocking Agents/antagonists & inhibitors , Allyl Compounds/chemistry , Aniline Compounds/chemistry , Crystallography, X-Ray , Structure-Activity Relationship
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