Sindhu Thangaraj
, Kāraikkudi

Bioinformatics, Biotechnology, Cancer Research

12.22

Publications

  • Sindhu Thangaraj · Srinivasan Pappu
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    ABSTRACT: Farnesoid X receptor and Takeda G-protein-coupled receptor-5 are well known bile acid receptors and act as promising targets for the drug development and treatment of diabetes. Agonists of both the bile acid receptors increase insulin sensitivity and control glucose, lipids and bile acid homeostasis. The current study deals with the identification of novel dual agonists using ligand and structure-based virtual screening. Initially, an experimentally proven well-known dual agonist of FXR and TGR5, namely INT-767, was docked into the binding sites of FXR and TGR5 to determine the protein residues important for ligand binding. The docked complexes FXRINT-767 and TGR5INT-767 were used to generate e-pharmacophore hypotheses. Ligand-based virtual screening was carried out using the hypothetical e-pharmacophore model against the ChemBridge database. Further, structure-based virtual screening was performed with screened hits to find potential agonists of FXR and TGR5. A total of four best agonists were identified based on their affinity and mode of interactions with the receptors. The binding mode of these compounds with both receptors was analyzed in detail. Furthermore, molecular dynamics, ADME toxicity prediction, density functional theory and binding free energy calculations were carried out to rank the compounds. Based on the above analyses, the most potent compound, ChemBridge_9149693, was selected for further in vitro studies. The results of in vitro assays suggested that ChemBridge_9149693 is a potent and promising drug for the treatment of type II diabetes. Thus, the compound could be used for further drug design and development of dual agonists of FXR and TGR5.
    Molecular BioSystems 03/2015; 11(5). DOI:10.1039/C5MB00137D · 3.18 Impact Factor
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    Thangaraj Sindhu · Pappu Srinivasan
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    ABSTRACT: TGR5, a G-protein coupled receptor, acts as a promising target for the treatment of diabetes, obesity and metabolic syndromes. Understanding the activation of TGR5, the structural conformation and the mode of mechanism upon binding with agonists is crucial for the development of new drugs. In the absence of experimental data, homology modeling was performed to predict the structure of TGR5. Molecular dynamics simulation of 100 ns was performed to investigate the stability of the constructed model embedded in a lipid bilayer. A combined method consisting of molecular docking and binding free energy calculations was performed to understand the binding mechanism of two experimentally proved selective TGR5 agonists. Additionally, 30 ns of protein–ligand complex dynamics were performed to reproduce the mechanism of interaction. Both agonists shared a similar binding mode and showed four common hydrogen bonding interactions with TGR5. Thus, the results could provide more knowledge on the activation of TGR5 by agonists and prove helpful in the development of novel potent agonists.
    RSC Advances 01/2015; 5(19):14202-14213. DOI:10.1039/c4ra16617e · 3.84 Impact Factor
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    Sindhu Thangaraj · Rajamanikandan Sundaraj · Pappu Srinivasan
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    ABSTRACT: The present study was designed to evaluate the antioxidant and antibacterial activity of methanol extract of Kyllinga nemoralis. Six different in vitro antioxidant assays including 2,2-diphenyl-1-picrylhydrazyl, hydroxyl radical, superoxide anion radical, hydrogen peroxide radical, ferric reducing antioxidant power assay and reducing power were carried out to ensure the scavenging effect of the plant on free radicals. In addition, total antioxidant capacity assay, total phenolic contents, tannins, flavonoids and flavonol contents of the plant were also analysed by the standard protocols. Kyllinga nemoralis exhibited high antioxidant activity on 2,2-diphenyl-1-picrylhydrazyl assay (IC50 =90µg/ml), superoxide radical scavenging assay (IC50 =180µg/ml) and hydrogen peroxide radical scavenging assay (IC50 = 200 µg/ml), compared with standards. These observations provide comprehensible supporting evidence for the antioxidant potential of the plant extract. Reducing power (IC50 =213.16 µg/ml) and hydroxyl radical scavenging activity (IC50 = 223 µg/ml) of the plant extract was remarkable. The methanol extract of K. nemoralis exhibited significant antimicrobial activity against Gram-positive human pathogenic bacteria. Standard in vitro antioxidant assays assessed the electron donating ability of the plant extract in scavenging free radicals. The inhibitory effect of the plant extract against bacterial pathogens may be due to the presence of phytochemicals. Thus, the results suggest that Kyllinga nemoralis is a potential source of antioxidants and could serve as the base for drug development.
    Indian Journal of Pharmaceutical Sciences 04/2014; · 0.30 Impact Factor
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    ABSTRACT: The present study was designed to evaluate the antioxidant and antibacterial activity of methanol extract of Kyllinga nemoralis. Six different in vitro antioxidant assays including 2,2-diphenyl-1-picrylhydrazyl, hydroxyl radical, superoxide anion radical, hydrogen peroxide radical, ferric reducing antioxidant power assay and reducing power were carried out to ensure the scavenging effect of the plant on free radicals. In addition, total antioxidant capacity assay, total phenolic contents, tannins, flavonoids and flavonol contents of the plant were also analysed by the standard protocols. Kyllinga nemoralis exhibited high antioxidant activity on 2,2-diphenyl-1-picrylhydrazyl assay (IC50= 90 μg/ml), superoxide radical scavenging assay (IC50= 180 μg/ml) and hydrogen peroxide radical scavenging assay (IC50= 200 μg/ml), compared with standards. These observations provide comprehensible supporting evidence for the antioxidant potential of the plant extract. Reducing power (IC50= 213.16 μg/ml) and hydroxyl radical scavenging activity (IC50= 223 μg/ml) of the plant extract was remarkable. The methanol extract of K. nemoralis exhibited significant antimicrobial activity against Gram-positive human pathogenic bacteria. Standard in vitro antioxidant assays assessed the electron donating ability of the plant extract in scavenging free radicals. The inhibitory effect of the plant extract against bacterial pathogens may be due to the presence of phytochemicals. Thus, the results suggest that Kyllinga nemoralis is a potential source of antioxidants and could serve as the base for drug development.
    Indian Journal of Pharmaceutical Sciences 03/2014; 76(2):170-4. · 0.30 Impact Factor
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    Thangaraj Sindhu · Pappu Srinivasan
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    ABSTRACT: Farnesoid X receptor (FXR) is a potential therapeutic target for the treatment of diabetes mellitus. Atom-based three-dimensional quantitative structure activity relationship (3D-QSAR) models were developed for a series of 48 benzimidazole-based agonists of FXR. A total of five pharmacophore hypotheses were generated based on the survival score to build QSAR models. HHHRR was considered as a best model that consisted of three hydrophobic features (H) and two aromatic rings (R). The best hypothesis, HHHRR yielded a 3D-QSAR model with good statistical value (R2) of 0.8974 for a training set of 39 compounds and also showed good predictive power with correlation coefficient (Q2) of 0.7559 for a test set of nine compounds. Furthermore, molecular docking simulation was performed to understand the binding affinity of 48 benzimidazole-based compounds against the active site of human FXR protein. Docking results revealed that both the most active and least active compounds showed similar binding mode to the experimentally observed binding mode of co-crystallized ligand. The generated 3D contour maps revealed the structure activity relationship of the compounds. Substitution effects at different positions of benzimidazole derivatives would lead to the discovery of new agonists against human FXR protein.
    Journal of Receptor and Signal Transduction Research 02/2014; 34(4). DOI:10.3109/10799893.2014.885048 · 1.61 Impact Factor
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    ABSTRACT: To evaluate the protective effect of ethanol extract of Mollugo nudicaulis (M. nudicaulis) against perchloroethylene-induced hepatotoxicity. The hepatoprotective activity of the ethanol extract of M. nudicaulis (200 mg/kg body wt) was studied in percholoroethylene (1 000 mg/kg body wt) induced hepatotoxicity in Wistar albino rats. The serum levels of AST, ALT, ALP, bilirubin and the liver content of SOD, CAT, GPx, GST, GSH, vitamin C were assessed to evaluate the hepatoprotective and antioxidant activities of the extract. The activity of the extract was compared with silymarin, a standard reference drug. In addition, serum urea, uric acid and creatinine levels were measured to evaluate the kidney function. The histopathological examination of the liver tissues was observed to support the biochemical parameters. The results revealed that the extract significantly (P<0.05) restored the serum levels of AST, ALT, ALP, bilirubin and significantly (P<0.05) increased the antioxidant enzymes SOD, CAT, GPx, GST, GSH, vitamin C in perchloroethylene-induced rats to its normalcy. The biochemical observations were supported by the histopathological studies of the liver tissues. The results led to the conclusion that M. nudicaulis possess hepatoprotective and antioxidant activites against perchloroethylene-induced hepatotoxicity in rats.
    Asian Pacific Journal of Tropical Medicine 11/2012; 5(11):862-7. DOI:10.1016/S1995-7645(12)60161-8 · 0.93 Impact Factor
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    Iranian journal of public health 08/2012; 41(7):24-33. · 0.24 Impact Factor
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    ABSTRACT: Computational identification of phylogenetic motifs helps to understand the knowledge about known functional features that includes catalytic site, substrate binding epitopes, and protein-protein interfaces. Furthermore, they are strongly conserved among orthologs, indicating their evolutionary importance. The study aimed to analyze five candidate genes involved in type II diabetic nephropathy and to predict phylogenetic motifs from their corresponding orthologous protein sequences. AKR1B1, APOE, ENPP1, ELMO1 and IGFBP1 are the genes that have been identified as an important target for type II diabetic nephropathy through experimental studies. Their corresponding protein sequences, structures, orthologous sequences were retrieved from UniprotKB, PDB, and PHOG database respectively. Multiple sequence alignments were constructed using ClustalW and phylogenetic motifs were identified using MINER. The occurrence of amino acids in the obtained phylogenetic motifs was generated using WebLogo and false positive expectations were calculated against phylogenetic similarity. In total, 17 phylogenetic motifs were identified from the five proteins and the residues such as glycine, leucine, tryptophan, aspartic acid were found in appreciable frequency whereas arginine identified in all the predicted PMs. The result implies that these residues can be important to the functional and structural role of the proteins and calculated false positive expectations implies that they were generally conserved in traditional sense. The prediction of phylogenetic motifs is an accurate method for detecting functionally important conserved residues. The conserved motifs can be used as a potential drug target for type II diabetic nephropathy.
    Iranian Journal of Public Health 07/2012; 41(7):24-33. · 0.58 Impact Factor
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    ABSTRACT: Mucins play critical roles and attractive targets for anticancer therapies. It is desirable to develop new types of small-molecule inhibitors of Mucins. In this study, the binding features of several inhibitors to mucins have been studied by molecular docking analyses. Bioactive compounds isolated from marine organisms which are very potent antioxidant, free radical scavenger have been extensively studied to expolore their potential utilization in chemoprevention. The main objective of the present work is to perform a docking analysis of bioactive compounds derived from marine bacteria and fungi into the Mucin (MUC1) active site to determine the probable binding model. Docking studies of these compounds were performed using Arguslab. QSAR studies have been implemented to predict the biological properties of the bioactive compounds. The results thus implied that 14-hydroxyterezine could lead to the development of novel inhibitors against MUC1 oncoprotein. The current work has potential for application in structure based MUC1 inhibitor discovery.
    International Journal of Pharmacy and Pharmaceutical Sciences 03/2011; 3. · 1.59 Impact Factor
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    ABSTRACT: The DEK proto‐oncogene has been associated with human carcinogenesis‐either as a fusion with the CAN nucleoporin protein or when transcriptionally upregulated. DEK is frequently upregulated in aggressive human tumors such as glioblastoma, melanoma and bladder carcinoma. A molecular docking of nine plants derived bioactive compounds with the oncoprotein DEK was performed using ArgusLab 4.0.1 and the differences in their binding modes were investigated. QSAR toxicity analysis has been performed for a series of plant derived nine bioactive compounds using FAF Drugs ADME/tox filtering server. Considering the molecular properties of the ligands, higher inhibitory activity is associated with reduced molecular flexibility, as measured by lower polar surface area (TPSA), LogP, lower hydrogen bond counts, confirming the capability of the bioactive compounds for binding at the active site of the receptor.
    Asian Journal of Pharmaceutical and Clinical Research 01/2011; 4:67-71. · 0.51 Impact Factor
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    ABSTRACT: Aim of the study was to investigate the comparative effect of ethanolic extracts of Justicia adhatoda, Mimosa pudica and Vitex negundo on hepatoprotective activity against Perchloroethylene induced liver damage in albino rats. Liver damage was induced by administration of Perchloroethylene (1000 mg/kg body weight). All the tested extracts showed potent hepatoprotective activity at 1000 mg/kg body weight test dose which was comparable with that of the standard silymarin used in similar test dose. The ethanolic extract was able to restore the biochemical levels to normal which were altered due to Perchloroethylene intoxication in albino rats.
    Pharmacologyonline 01/2011; 1:481-491. · 0.16 Impact Factor
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    ABSTRACT: The present study was designed to investigate the in alloxan (120 mg/kg b.wt) induced diabetic rats. The ethanolic extract of the whole plant of Mollugo nudicaulis (200mg/kg) administered orally to the diabetic rats for 21 days, produced significant decrease in the level of blood glucose, cholesterol, triglycerides, low density lipoprotein (LDL), lipid peroxidation, liver glycogen, serum creatinine, urea, uric acid and liver marker enzymes such as AST, ALT, ALP. It also produced significant increase in High density lipoprotein (HDL), Superoxide dismutase (SOD), Catalase (CAT), Glutathione peroxidase (GPx), Glutathione-S-Transferase (GST), Reduced glutathione (GSH), Vitamin C, which clearly show the antioxidant property of extract. The effect of the ethanolic the extract of Mollugo nudicaulis was compared with the standard drug Glibenclamide (1.25mg/kg b.wt).

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