28 results on '"Sridevi, S."'
Search Results
2. Metabolism of Tembotrione, a Triketone Herbicide, confers Differential Sensitivity in Winter Wheat ( Triticum aestivum ).
- Author
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Sudhakar S, Nakka S, Mohammad A, Trick HN, Prasad PVV, and Jugulam M
- Subjects
- Triticum genetics, Triticum metabolism, Cyclohexanones pharmacology, Sulfones pharmacology, Cytochrome P-450 Enzyme System metabolism, Zea mays metabolism, Herbicides pharmacology, Herbicides metabolism
- Abstract
Tembotrione is a triketone herbicide widely used for broad-spectrum weed control in corn but not registered for use in wheat. A wide collection of spring, winter, and EMS-derived mutant lines of wheat was evaluated for their response to tembotrione treatment. Two winter wheat (WW) genotypes (WW-1 and WW-2) were found to be least sensitive to this herbicide, surviving >6 times the field recommended dose (92 g ai ha
-1 ) compared to the most sensitive genotype (WW-24). Further, HPLC analysis using [14 C] tembotrione suggested that both WW-1 and WW-2 metabolized tembotrione rapidly to nontoxic metabolites. Pretreatment with a P450 inhibitor (malathion) followed by tembotrione application increased the sensitivity of WW-1 and WW-2 genotypes to this herbicide, suggesting likely involvement of P450 enzymes in metabolizing tembotrione similar to corn. Overall, our results suggest that the genotypes WW-1 and WW-2 can potentially be used to develop tembotrione-resistant wheat varieties.- Published
- 2024
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3. Correction to "Indole-3-acetamides: As Potential Antihyperglycemic and Antioxidant Agents; Synthesis, In Vitro α -Amylase Inhibitory Activity, Structure-Activity Relationship, and In Silico Studies".
- Author
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Kanwal, Khan KM, Chigurupati S, Ali F, Younus M, Aldubayan M, Wadood A, Khan H, Taha M, and Perveen S
- Abstract
[This corrects the article DOI: 10.1021/acsomega.0c05581.]., (© 2021 The Authors. Published by American Chemical Society.)
- Published
- 2021
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4. Antibacterial and Antibiofouling Activities of Antimicrobial Peptide-Functionalized Graphene-Silver Nanocomposites for the Inhibition and Disruption of Staphylococcus aureus Biofilms.
- Author
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Parandhaman T, Choudhary P, Ramalingam B, Schmidt M, Janardhanam S, and Das SK
- Subjects
- Animals, Anti-Bacterial Agents pharmacology, Antimicrobial Peptides, Biofilms, Rats, Silver pharmacology, Staphylococcus aureus, Graphite, Nanocomposites, Staphylococcal Infections drug therapy
- Abstract
Owing to the emergence of antibiotic-resistant strains, bacterial infection and biofilm formation are growing concerns in healthcare management. Herein, we report an eco-benign strategy for the synthesis and functionalization of graphene-silver (rGOAg) nanocomposites with an antimicrobial peptide (AMP) for the treatment of Staphylococcus aureus infection. The synthesis of rGOAg nanocomposites was carried out by simple microwave reduction, and the as-synthesized rGOAg was covalently functionalized with an AMP. As a natural AMP, poly-l-lysine (PLL) functionalization of rGOAg enhanced the antibacterial efficacy and target specificity against the S. aureus biofilm. The robust bactericidal efficiency and biofilm disruption by AMP-functionalized rGOAg (designated as GAAP) occurred through the "contact-kill-release" mode of action, where the electrostatic interaction with bacterial cells together with intracellular ROS generation induced physical disruption to the cell membrane. The internalization of GAAP into the cytoplasm through the damaged cell membrane caused an outburst of intracellular proteins and DNA. Crystal violet staining along with fluorescence and confocal microscopic images showed an effective inhibition and disruption of the S. aureus biofilm upon treatment with GAAP. PLL functionalization also prevented the dissolution of Ag
+ ions and thereby minimized the in vitro toxicity of GAAP to the 3 T6 fibroblast and human red blood cells. The ex vivo rat skin disinfection model further demonstrated the potency of GAAP in eliminating the biofilm formation and disruption of the S. aureus biofilm. The obtained results demonstrated a general approach for designing a functional nanocomposite material to disrupt the mature biofilm and provided a promising strategy for treating bacterial infection.- Published
- 2021
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5. Substituted Benzimidazole Analogues as Potential α-Amylase Inhibitors and Radical Scavengers.
- Author
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Akande AA, Salar U, Khan KM, Syed S, Aboaba SA, Chigurupati S, Wadood A, Riaz M, Taha M, Bhatia S, Kanwal, Shamim S, and Perveen S
- Abstract
Benzimidazole scaffolds are known to have a diverse range of biological activities and found to be antidiabetic and antioxidant. In this study, a variety of arylated benzimidazoles 1 - 31 were synthesized. Except for compounds 1 , 6 , 7 , and 8 , all are new derivatives. All compounds were screened for α-amylase inhibitory, 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activities. In vitro screening results revealed that all molecules demonstrated significant α-amylase inhibition with IC
50 values of 1.86 ± 0.08 to 3.16 ± 0.31 μM as compared to standard acarbose (IC50 = 1.46 ± 0.26 μM). However, compounds showed significant ABTS and DPPH radical scavenging potentials with IC50 values in the range of 1.37 ± 0.21 to 4.00 ± 0.10 μM for ABTS and 1.36 ± 0.09 to 3.60 ± 0.20 μM for DPPH radical scavenging activities when compared to ascorbic acid with IC50 values of 0.72 ± 0.21 and 0.73 ± 0.05 μM for ABTS and DPPH radical scavenging potentials, respectively. Structure-activity relationship (SAR) was established after critical analysis of varying substitution effects on α-amylase inhibitory and radical scavenging (ABTS and DPPH) potentials. However, molecular docking was also performed to figure out the active participation of different groups of synthetic molecules during binding with the active pocket of the α-amylase enzyme., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)- Published
- 2021
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6. Indole-3-acetamides: As Potential Antihyperglycemic and Antioxidant Agents; Synthesis, In Vitro α-Amylase Inhibitory Activity, Structure-Activity Relationship, and In Silico Studies.
- Author
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Kanwal, Khan KM, Chigurupati S, Ali F, Younus M, Aldubayan M, Wadood A, Khan H, Taha M, and Perveen S
- Abstract
Indole-3-acetamides ( 1-24 ) were synthesized via coupling of indole-3-acetic acid with various substituted anilines in the presence of coupling reagent 1,1-carbonyldiimidazole. The structures of synthetic molecules were elucidated through different spectroscopic techniques including electron ionization-mass spectroscopy (EI-MS),
1 H-,13 C NMR, and high-resolution EI-MS (HREI-MS). These compounds were screened for their antihyperglycemic and antioxidant potentials. All compounds displayed good to moderate inhibition against α-amylase enzyme with IC50 values ranging between 1.09 ± 0.11 and 2.84 ± 0.1 μM compared to the standard acarbose (IC50 = 0.92 ± 0.4 μM). Compound 15 (IC50 = 1.09 ± 0.11 μM) was the most active compound of the series and exhibited good inhibition against α-amylase; in addition, this compound also exhibited good antioxidant potential with IC50 values of 0.35 ± 0.1 and 0.81 ± 0.25 μM in 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays, respectively. The binding interactions of synthetic molecules with the enzyme's active site were confirmed via in silico studies. The current study had identified a number of lead molecules as potential antihyperglycemic and antioxidant agents., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)- Published
- 2021
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7. Screening of Focused Compound Library Targeting Liver X Receptors in Pancreatic Cancer Identified Ligands with Inverse Agonist and Degrader Activity.
- Author
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Karaboga H, Huang W, Srivastava S, Widmann S, Addanki S, Gamage KT, Mazhar Z, Ebalunode JO, Briggs JM, Gustafsson JÅ, Filgueira CS, Gilbertson SR, and Lin CY
- Subjects
- Antineoplastic Agents chemistry, Carcinoma, Pancreatic Ductal metabolism, Cell Line, Tumor, Drug Inverse Agonism, Humans, Ligands, Liver X Receptors agonists, Pancreatic Neoplasms metabolism, Proteolysis drug effects, Small Molecule Libraries chemistry, Antineoplastic Agents pharmacology, Carcinoma, Pancreatic Ductal drug therapy, Liver X Receptors metabolism, Pancreatic Neoplasms drug therapy, Small Molecule Libraries pharmacology
- Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the predominant form of pancreatic cancer. PDACs harbor oncogenic mutations in the KRAS gene, and ongoing efforts to directly target its mutant protein product to inhibit tumor growth are a priority not only in pancreatic cancer but in other malignancies such as lung and colorectal cancers where KRAS is also commonly mutated. An alternative strategy to directly targeting KRAS is to identify and target druggable receptors involved in dysregulated cancer hallmarks downstream of KRAS dysregulation. Liver X receptors (LXRs) are members of the nuclear receptor family of ligand-modulated transcription factors and are involved in the regulation of genes which function in key cancer-related processes, including cholesterol transport, lipid and glucose metabolism, and inflammatory and immune responses. Modulation of LXRs via small molecule ligands has emerged as a promising approach for directly targeting tumor cells or the stromal and immune cells within the tumor microenvironment. We have previously shown that only one of the two LXR subtypes (LXRβ) is expressed in pancreatic cancer cells, and targeting LXR with available synthetic ligands blocked the proliferation of PDAC cells and tumor formation. In a screen of a focused library of drug-like small molecules predicted to dock in the ligand-binding pocket of LXRβ, we identified two novel LXR ligands with more potent antitumor activity than current LXR agonists used in our published studies. Characterization of the two lead compounds (GAC0001E5 and GAC0003A4) indicates that they function as LXR inverse agonists which inhibit their transcriptional activity. Prolonged treatments with novel ligands further revealed their function as LXR "degraders" which significantly reduced LXR protein levels in all three PDAC cell lines tested. These findings support the utility of these novel inhibitors in basic research on ligand design, allosteric mechanisms, and LXR functions and their potential application as treatments for advanced pancreatic cancer and other recalcitrant malignancies.
- Published
- 2020
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8. Long-Lasting and Fast-Acting in Vivo Efficacious Antiplasmodial Azepanylcarbazole Amino Alcohol.
- Author
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Abla N, Bashyam S, Charman SA, Greco B, Hewitt P, Jiménez-Díaz MB, Katneni K, Kubas H, Picard D, Sambandan Y, Sanz L, Smith D, Wang T, Willis P, Wittlin S, and Spangenberg T
- Abstract
With ∼429,000 deaths in 2016, malaria remains a major infectious disease where the need to treat the fever symptoms, but also to provide relevant post-treatment prophylaxis, is of major importance. An azepanylcarbazole amino alcohol is disclosed with a long- and fast-acting in vivo antiplasmodial efficacy and meets numerous attributes of a desired post-treatment chemoprophylactic antimalarial agent. The synthesis, the parasitological characterization, and the animal pharmacokinetics and pharmacodynamics of this compound are presented along with a proposed target., Competing Interests: The authors declare no competing financial interest.
- Published
- 2017
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9. One-Bead-Two-Compound Thioether Bridged Macrocyclic γ-AApeptide Screening Library against EphA2.
- Author
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Shi Y, Challa S, Sang P, She F, Li C, Gray GM, Nimmagadda A, Teng P, Odom T, Wang Y, van der Vaart A, Li Q, and Cai J
- Subjects
- Cell Line, Tumor, Cell Movement drug effects, Enzyme Assays, Humans, Molecular Dynamics Simulation, Peptides, Cyclic chemical synthesis, Peptides, Cyclic metabolism, Peptidomimetics chemical synthesis, Peptidomimetics metabolism, Protein Binding, Receptor, EphA2 metabolism, Sulfides chemical synthesis, Sulfides metabolism, Sulfides pharmacology, Peptide Library, Peptides, Cyclic pharmacology, Peptidomimetics pharmacology, Receptor, EphA2 antagonists & inhibitors
- Abstract
Identification of molecular ligands that recognize peptides or proteins is significant but poses a fundamental challenge in chemical biology and biomedical sciences. Development of cyclic peptidomimetic library is scarce, and thus discovery of cyclic peptidomimetic ligands for protein targets is rare. Herein we report the unprecedented one-bead-two-compound (OBTC) combinatorial library based on a novel class of the macrocyclic peptidomimetics γ-AApeptides. In the library, we utilized the coding peptide tags synthesized with Dde-protected α-amino acids, which were orthogonal to solid phase synthesis of γ-AApeptides. Employing the thioether linkage, the desired macrocyclic γ-AApeptides were found to be effective for ligand identification. Screening the library against the receptor tyrosine kinase EphA2 led to the discovery of one lead compound that tightly bound to EphA2 (K
d = 81 nM) and potently antagonized EphA2-mediated signaling. This new approach of macrocyclic peptidomimetic library may lead to a novel platform for biomacromolecular surface recognition and function modulation.- Published
- 2017
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10. Identification of a Potential Antimalarial Drug Candidate from a Series of 2-Aminopyrazines by Optimization of Aqueous Solubility and Potency across the Parasite Life Cycle.
- Author
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Le Manach C, Nchinda AT, Paquet T, Gonzàlez Cabrera D, Younis Y, Han Z, Bashyam S, Zabiulla M, Taylor D, Lawrence N, White KL, Charman SA, Waterson D, Witty MJ, Wittlin S, Botha ME, Nondaba SH, Reader J, Birkholtz LM, Jiménez-Díaz MB, Martínez MS, Ferrer S, Angulo-Barturen I, Meister S, Antonova-Koch Y, Winzeler EA, Street LJ, and Chibale K
- Subjects
- Animals, Antimalarials chemistry, Antimalarials metabolism, Disease Models, Animal, Dose-Response Relationship, Drug, Ether-A-Go-Go Potassium Channels antagonists & inhibitors, Ether-A-Go-Go Potassium Channels metabolism, Hep G2 Cells, Humans, Mice, Mice, SCID, Microsomes, Liver chemistry, Microsomes, Liver metabolism, Molecular Structure, Parasitic Diseases, Animal parasitology, Parasitic Sensitivity Tests, Plasmodium berghei growth & development, Plasmodium falciparum growth & development, Pyrazines chemistry, Pyrazines metabolism, Solubility, Structure-Activity Relationship, Water chemistry, Antimalarials pharmacology, Life Cycle Stages drug effects, Malaria drug therapy, Parasitic Diseases, Animal drug therapy, Plasmodium berghei drug effects, Plasmodium falciparum drug effects, Pyrazines pharmacology
- Abstract
Introduction of water-solubilizing groups on the 5-phenyl ring of a 2-aminopyrazine series led to the identification of highly potent compounds against the blood life-cycle stage of the human malaria parasite Plasmodium falciparum. Several compounds displayed high in vivo efficacy in two different mouse models for malaria, P. berghei-infected mice and P. falciparum-infected NOD-scid IL-2Rγ
null mice. One of the frontrunners, compound 3, was identified to also have good pharmacokinetics and additionally very potent activity against the liver and gametocyte parasite life-cycle stages.- Published
- 2016
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11. Hit-to-Lead Studies for the Antimalarial Tetrahydroisoquinolone Carboxanilides.
- Author
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Floyd DM, Stein P, Wang Z, Liu J, Castro S, Clark JA, Connelly M, Zhu F, Holbrook G, Matheny A, Sigal MS, Min J, Dhinakaran R, Krishnan S, Bashyum S, Knapp S, and Guy RK
- Subjects
- Anilides chemical synthesis, Anilides pharmacology, Anilides toxicity, Animals, Antimalarials chemical synthesis, Antimalarials pharmacology, Antimalarials toxicity, Coculture Techniques, Erythrocytes cytology, Erythrocytes parasitology, Humans, Isoquinolines chemical synthesis, Isoquinolines pharmacology, Isoquinolines toxicity, Mice, Microsomes, Liver metabolism, Plasmodium falciparum physiology, Solubility, Stereoisomerism, Structure-Activity Relationship, Anilides chemistry, Antimalarials chemistry, Isoquinolines chemistry, Plasmodium falciparum drug effects
- Abstract
Phenotypic whole-cell screening in erythrocytic cocultures of Plasmodium falciparum identified a series of dihydroisoquinolones that possessed potent antimalarial activity against multiple resistant strains of P. falciparum in vitro and show no cytotoxicity to mammalian cells. Systematic structure-activity studies revealed relationships between potency and modifications at N-2, C-3, and C-4. Careful structure-property relationship studies, coupled with studies of metabolism, addressed the poor aqueous solubility and metabolic vulnerability, as well as potential toxicological effects, inherent in the more potent primary screening hits such as 10b. Analogues 13h and 13i, with structural modifications at each site, were shown to possess excellent antimalarial activity in vivo. The (+)-(3S,4S) enantiomer of 13i and similar analogues were identified as the more potent. On the basis of these studies, we have selected (+)-13i for further study as a preclinical candidate.
- Published
- 2016
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12. Combined High-Density Lipoprotein Proteomic and Glycomic Profiles in Patients at Risk for Coronary Artery Disease.
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Krishnan S, Huang J, Lee H, Guerrero A, Berglund L, Anuurad E, Lebrilla CB, and Zivkovic AM
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- Adult, Aged, Atherosclerosis blood, Case-Control Studies, Coronary Angiography, Coronary Artery Disease diagnosis, Female, Gangliosides analysis, Glycomics methods, Humans, Lipoproteins, HDL analysis, Lipoproteins, HDL chemistry, Male, Middle Aged, Principal Component Analysis, Proteomics methods, Random Allocation, Risk Factors, Coronary Artery Disease blood, Lipoproteins, HDL blood
- Abstract
Objectives: To test whether recently developed methods for comprehensive profiling of the high-density lipoprotein (HDL) glycome combined with the HDL proteome can distinguish individuals with coronary artery disease (CAD) from those without., Methods: Twenty subjects at risk for CAD, who underwent diagnostic coronary arteriography, were analyzed. Ten subjects had CAD, and ten did not. HDL was extracted from fasting plasma samples by ultracentrifugation, followed by shotgun proteomic, glycomic, and ganglioside analyses using LC-MS. CAD vs non-CAD subjects' data were compared using univariate and multivariate statistics., Results: Principal components analysis showed a clear separation of CAD and non-CAD subjects, confirming that combined HDL proteomic and glycomic profiles distinguished at-risk subjects with atherosclerosis from those without. CAD patients had lower HDL apolipoprotein content (specifically ApoA-I, A-II, and E, p < 0.05), and lower serum amyloid A2 (SAA2, p = 0.020) and SAA4 (p = 0.007) but higher sialylated glycans (p < 0.05)., Conclusion: Combined proteomic and glycomic profiling of isolated HDL was tested as a novel analytical approach for developing biomarkers of disease. In this pilot study we found that HDL proteome and glycome distinguished between individuals who had CAD from those who did not within a group of individuals equally at risk for heart disease.
- Published
- 2015
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13. A Novel Pyrazolopyridine with in Vivo Activity in Plasmodium berghei- and Plasmodium falciparum-Infected Mouse Models from Structure-Activity Relationship Studies around the Core of Recently Identified Antimalarial Imidazopyridazines.
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Le Manach C, Paquet T, Brunschwig C, Njoroge M, Han Z, Gonzàlez Cabrera D, Bashyam S, Dhinakaran R, Taylor D, Reader J, Botha M, Churchyard A, Lauterbach S, Coetzer TL, Birkholtz LM, Meister S, Winzeler EA, Waterson D, Witty MJ, Wittlin S, Jiménez-Díaz MB, Santos Martínez M, Ferrer S, Angulo-Barturen I, Street LJ, and Chibale K
- Subjects
- Animals, Antimalarials pharmacokinetics, Antimalarials pharmacology, Ether-A-Go-Go Potassium Channels metabolism, Humans, Liver parasitology, Malaria parasitology, Malaria, Falciparum drug therapy, Malaria, Falciparum parasitology, Mice, Pyrazoles pharmacokinetics, Pyrazoles pharmacology, Pyridines pharmacokinetics, Pyridines pharmacology, Rats, Structure-Activity Relationship, Antimalarials chemistry, Antimalarials therapeutic use, Malaria drug therapy, Plasmodium berghei drug effects, Plasmodium falciparum drug effects, Pyrazoles chemistry, Pyrazoles therapeutic use, Pyridines chemistry, Pyridines therapeutic use
- Abstract
Toward improving pharmacokinetics, in vivo efficacy, and selectivity over hERG, structure-activity relationship studies around the central core of antimalarial imidazopyridazines were conducted. This study led to the identification of potent pyrazolopyridines, which showed good in vivo efficacy and pharmacokinetics profiles. The lead compounds also proved to be very potent in the parasite liver and gametocyte stages, which makes them of high interest.
- Published
- 2015
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14. Multiple e-pharmacophore modeling, 3D-QSAR, and high-throughput virtual screening of hepatitis C virus NS5B polymerase inhibitors.
- Author
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Therese PJ, Manvar D, Kondepudi S, Battu MB, Sriram D, Basu A, Yogeeswari P, and Kaushik-Basu N
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- Antiviral Agents adverse effects, Antiviral Agents chemistry, Antiviral Agents pharmacokinetics, Antiviral Agents pharmacology, Cell Line, Drug Evaluation, Preclinical, Enzyme Inhibitors adverse effects, Enzyme Inhibitors pharmacokinetics, Hepacivirus drug effects, High-Throughput Screening Assays, Humans, Protein Conformation, Thermodynamics, Viral Nonstructural Proteins chemistry, Viral Nonstructural Proteins metabolism, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Hepacivirus enzymology, Molecular Docking Simulation, Quantitative Structure-Activity Relationship, User-Computer Interface, Viral Nonstructural Proteins antagonists & inhibitors
- Abstract
The hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRP) is a crucial and unique component of the HCV RNA replication machinery and a validated target for drug discovery. Multiple crystal structures of NS5B inhibitor complexes have facilitated the identification of novel compound scaffolds through in silico analysis. With the goal of discovering new NS5B inhibitor leads, HCV NS5B crystal structures bound with inhibitors in the palm and thumb allosteric pockets in combination with ligands with known inhibitory potential were explored for a comparative pharmacophore analyses. The energy-based and 3D-QSAR-based pharmacophore models were validated using enrichment analysis, and the six models thus developed were employed for high-throughput virtual screening and docking to identify nonpeptidic leads. The hits derived at each stage were analyzed for diversity based on the six pharmacophore models, followed by molecular docking and filtering based on their interaction with amino acids in the NS5B allosteric pocket and 3D-QSAR predictions. The resulting 10 hits displaying diverse scaffold were then screened employing biochemical and cell-based NS5B and anti-HCV inhibition assays. Of these, two molecules H-5 and H-6 were the most promising, exhibiting IC50 values of 28.8 and 47.3 μM against NS5B polymerase and anti-HCV inhibition of 96% and 86% at 50 μM, respectively. The identified leads comprised of benzimidazole (H-5) and pyridine (H-6) scaffolds thus constitute prototypical molecules for further optimization and development as NS5B inhibitors.
- Published
- 2014
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15. 2,4-Diaminothienopyrimidines as orally active antimalarial agents.
- Author
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González Cabrera D, Le Manach C, Douelle F, Younis Y, Feng TS, Paquet T, Nchinda AT, Street LJ, Taylor D, de Kock C, Wiesner L, Duffy S, White KL, Zabiulla KM, Sambandan Y, Bashyam S, Waterson D, Witty MJ, Charman SA, Avery VM, Wittlin S, and Chibale K
- Subjects
- Administration, Oral, Animals, Antimalarials chemistry, Antimalarials pharmacology, Cell Line, Databases, Chemical, Drug Resistance, Multiple, ERG1 Potassium Channel, Ether-A-Go-Go Potassium Channels antagonists & inhibitors, High-Throughput Screening Assays, Humans, Malaria drug therapy, Malaria parasitology, Male, Mice, Microsomes, Liver metabolism, Plasmodium berghei, Plasmodium falciparum drug effects, Pyrimidines chemistry, Pyrimidines pharmacology, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Thiophenes chemistry, Thiophenes pharmacology, Antimalarials chemical synthesis, Pyrimidines chemical synthesis, Thiophenes chemical synthesis
- Abstract
A novel series of 2,4-diaminothienopyrimidines with potential as antimalarials was identified from whole-cell high-throughput screening of a SoftFocus ion channel library. Synthesis and structure-activity relationship studies identified compounds with potent antiplasmodial activity and low in vitro cytotoxicity. Several of these analogues exhibited in vivo activity in the Plasmodium berghei mouse model when administered orally. However, inhibition of the hERG potassium channel was identified as a liability for this series.
- Published
- 2014
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16. Comprehensive multiphase NMR spectroscopy of intact ¹³C-labeled seeds.
- Author
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Lam L, Soong R, Sutrisno A, de Visser R, Simpson MJ, Wheeler HL, Campbell M, Maas WE, Fey M, Gorissen A, Hutchins H, Andrew B, Struppe J, Krishnamurthy S, Kumar R, Monette M, Stronks HJ, Hume A, and Simpson AJ
- Subjects
- Brassica chemistry, Carbon Isotopes, Glycerides chemistry, Isotope Labeling, Magnetic Resonance Spectroscopy instrumentation, Triticum chemistry, Zea mays chemistry, Magnetic Resonance Spectroscopy methods, Seeds chemistry
- Abstract
Seeds are complex entities composed of liquids, gels, and solids. NMR spectroscopy is a powerful tool for studying molecular structure but has evolved into two fields, solution and solid state. Comprehensive multiphase (CMP) NMR spectroscopy is capable of liquid-, gel-, and solid-state experiments for studying intact samples where all organic components are studied and differentiated in situ. Herein, intact (13)C-labeled seeds were studied by a variety of 1D/2D (1)H/(13)C experiments. In the mobile phase, an assortment of metabolites in a single (13)C-labeled wheat seed were identified; the gel phase was dominated by triacylglycerides; the semisolid phase was composed largely of carbohydrate biopolymers, and the solid phase was greatly influenced by starchy endosperm signals. Subsequently, the seeds were compared and relative similarities and differences between seed types discussed. This study represents the first application of CMP-NMR to food chemistry and demonstrates its general utility and feasibility for studying intact heterogeneous samples.
- Published
- 2014
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17. Structure-activity-relationship studies around the 2-amino group and pyridine core of antimalarial 3,5-diarylaminopyridines lead to a novel series of pyrazine analogues with oral in vivo activity.
- Author
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Younis Y, Douelle F, González Cabrera D, Le Manach C, Nchinda AT, Paquet T, Street LJ, White KL, Zabiulla KM, Joseph JT, Bashyam S, Waterson D, Witty MJ, Wittlin S, Charman SA, and Chibale K
- Subjects
- Administration, Oral, Aminopyridines administration & dosage, Aminopyridines chemistry, Animals, Antimalarials administration & dosage, Antimalarials chemistry, CHO Cells, Cricetulus, Disease Models, Animal, Dose-Response Relationship, Drug, Humans, Mice, Microsomes, Liver chemistry, Microsomes, Liver metabolism, Molecular Structure, Parasitic Sensitivity Tests, Rats, Structure-Activity Relationship, Aminopyridines pharmacology, Antimalarials pharmacology, Plasmodium berghei drug effects, Plasmodium falciparum drug effects
- Abstract
Replacement of the pyridine core of antimalarial 3,5-diaryl-2-aminopyridines led to the identification of a novel series of pyrazine analogues with potent oral antimalarial activity. However, other changes to the pyridine core and replacement or substitution of the 2-amino group led to loss of antimalarial activity. The 3,5-diaryl-2-aminopyrazine series showed impressive in vitro antiplasmodial activity against the K1 (multidrug resistant) and NF54 (sensitive) strains of Plasmodium falciparum in the nanomolar IC50 range of 6-94 nM while also demonstrating good in vitro metabolic stability in human liver microsomes. In the Plasmodium berghei mouse model, this series generally exhibited good efficacy at low oral doses. One of the frontrunner compounds, 4, displayed potent in vitro antiplasmodial activity with IC50 values of 8.4 and 10 nM against the K1 and NF54 strains, respectively. When evaluated in P. berghei -infected mice, compound 4 was completely curative at an oral dose of 4 × 10 mg/kg.
- Published
- 2013
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18. Structure-activity relationship studies of orally active antimalarial 3,5-substituted 2-aminopyridines.
- Author
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González Cabrera D, Douelle F, Younis Y, Feng TS, Le Manach C, Nchinda AT, Street LJ, Scheurer C, Kamber J, White KL, Montagnat OD, Ryan E, Katneni K, Zabiulla KM, Joseph JT, Bashyam S, Waterson D, Witty MJ, Charman SA, Wittlin S, and Chibale K
- Subjects
- Administration, Oral, Aminopyridines chemistry, Aminopyridines pharmacology, Animals, Antimalarials chemistry, Antimalarials pharmacology, Drug Resistance, Multiple, ERG1 Potassium Channel, Ether-A-Go-Go Potassium Channels antagonists & inhibitors, Humans, Malaria drug therapy, Mice, Microsomes, Liver metabolism, Plasmodium berghei, Plasmodium falciparum drug effects, Solubility, Structure-Activity Relationship, Aminopyridines chemical synthesis, Antimalarials chemical synthesis
- Abstract
In an effort to address potential cardiotoxicity liabilities identified with earlier frontrunner compounds, a number of new 3,5-diaryl-2-aminopyridine derivatives were synthesized. Several compounds exhibited potent antiplasmodial activity against both the multidrug resistant (K1) and sensitive (NF54) strains in the low nanomolar range. Some compounds displayed a significant reduction in potency in the hERG channel inhibition assay compared to previously reported frontrunner analogues. Several of these new analogues demonstrated promising in vivo efficacy in the Plasmodium berghei mouse model and will be further evaluated as potential clinical candidates. The SAR for in vitro antiplasmodial and hERG activity was delineated.
- Published
- 2012
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19. Occurrence and toxicity of disinfection byproducts in European drinking waters in relation with the HIWATE epidemiology study.
- Author
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Jeong CH, Wagner ED, Siebert VR, Anduri S, Richardson SD, Daiber EJ, McKague AB, Kogevinas M, Villanueva CM, Goslan EH, Luo W, Isabelle LM, Pankow JF, Grazuleviciene R, Cordier S, Edwards SC, Righi E, Nieuwenhuijsen MJ, and Plewa MJ
- Subjects
- Animals, CHO Cells, Cell Survival drug effects, Cricetinae, Cricetulus, DNA Damage, Environmental Monitoring, Europe epidemiology, Female, Humans, Pregnancy, Pregnancy Outcome epidemiology, Disinfection, Drinking Water analysis, Water Pollutants, Chemical analysis, Water Pollutants, Chemical toxicity
- Abstract
The HIWATE (Health Impacts of long-term exposure to disinfection byproducts in drinking WATEr) project was a systematic analysis that combined the epidemiology on adverse pregnancy outcomes and other health effects with long-term exposure to low levels of drinking water disinfection byproducts (DBPs) in the European Union. The present study focused on the relationship of the occurrence and concentration of DBPs with in vitro mammalian cell toxicity. Eleven drinking water samples were collected from five European countries. Each sampling location corresponded with an epidemiological study for the HIWATE program. Over 90 DBPs were identified; the range in the number of DBPs and their levels reflected the diverse collection sites, different disinfection processes, and the different characteristics of the source waters. For each sampling site, chronic mammalian cell cytotoxicity correlated highly with the numbers of DBPs identified and the levels of DBP chemical classes. Although there was a clear difference in the genotoxic responses among the drinking waters, these data did not correlate as well with the chemical analyses. Thus, the agents responsible for the genomic DNA damage observed in the HIWATE samples may be due to unresolved associations of combinations of identified DBPs, unknown emerging DBPs that were not identified, or other toxic water contaminants. This study represents the first to integrate quantitative in vitro toxicological data with analytical chemistry and human epidemiologic outcomes for drinking water DBPs.
- Published
- 2012
- Full Text
- View/download PDF
20. In-situ molecular-level elucidation of organofluorine binding sites in a whole peat soil.
- Author
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Longstaffe JG, Courtier-Murias D, Soong R, Simpson MJ, Maas WE, Fey M, Hutchins H, Krishnamurthy S, Struppe J, Alaee M, Kumar R, Monette M, Stronks HJ, and Simpson AJ
- Subjects
- Albumins chemistry, Albumins metabolism, Binding Sites, Caprylates chemistry, Caprylates metabolism, Fluorine Compounds analysis, Fluorine Compounds metabolism, Fluorine Radioisotopes, Fluorocarbons chemistry, Fluorocarbons metabolism, Humic Substances analysis, Lignin chemistry, Lignin metabolism, Fluorine Compounds chemistry, Magnetic Resonance Spectroscopy methods, Soil chemistry
- Abstract
The chemical nature of xenobiotic binding sites in soils is of vital importance to environmental biogeochemistry. Interactions between xenobiotics and the naturally occurring organic constituents of soils are strongly correlated to environmental persistence, bioaccessibility, and ecotoxicity. Nevertheless, because of the complex structural and chemical heterogeneity of soils, studies of these interactions are most commonly performed indirectly, using correlative methods, fractionation, or chemical modification. Here we identify the organic components of an unmodified peat soil where some organofluorine xenobiotic compounds interact using direct molecular-level methods. Using (19)F→(1)H cross-polarization magic angle spinning (CP-MAS) nuclear magnetic resonance (NMR) spectroscopy, the (19)F nuclei of organofluorine compounds are used to induce observable transverse magnetization in the (1)H nuclei of organic components of the soil with which they interact after sorption. The observed (19)F→(1)H CP-MAS spectra and dynamics are compared to those produced using model soil organic compounds, lignin and albumin. It is found that lignin-like components can account for the interactions observed in this soil for heptafluoronaphthol (HFNap) while protein structures can account for the interactions observed for perfluorooctanoic acid (PFOA). This study employs novel comprehensive multi-phase (CMP) NMR technology that permits the application of solution-, gel-, and solid-state NMR experiments on intact soil samples in their swollen state.
- Published
- 2012
- Full Text
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21. 3,5-Diaryl-2-aminopyridines as a novel class of orally active antimalarials demonstrating single dose cure in mice and clinical candidate potential.
- Author
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Younis Y, Douelle F, Feng TS, González Cabrera D, Le Manach C, Nchinda AT, Duffy S, White KL, Shackleford DM, Morizzi J, Mannila J, Katneni K, Bhamidipati R, Zabiulla KM, Joseph JT, Bashyam S, Waterson D, Witty MJ, Hardick D, Wittlin S, Avery V, Charman SA, and Chibale K
- Subjects
- Administration, Oral, Aminopyridines pharmacokinetics, Aminopyridines pharmacology, Animals, Antimalarials pharmacokinetics, Antimalarials pharmacology, Biological Availability, Cell Line, Chloroquine pharmacology, Cytochrome P-450 Enzyme Inhibitors, Drug Resistance, ERG1 Potassium Channel, Ether-A-Go-Go Potassium Channels antagonists & inhibitors, Female, Humans, Isoenzymes antagonists & inhibitors, Malaria drug therapy, Mice, Microsomes, Liver metabolism, Plasmodium berghei, Plasmodium falciparum drug effects, Rabbits, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Aminopyridines chemical synthesis, Antimalarials chemical synthesis
- Abstract
A novel class of orally active antimalarial 3,5-diaryl-2-aminopyridines has been identified from phenotypic whole cell high-throughput screening of a commercially available SoftFocus kinase library. The compounds were evaluated in vitro for their antiplasmodial activity against K1 (chloroquine and drug-resistant strain) and NF54 (chloroquine-susceptible strain) as well as for their cytotoxicity. Synthesis and structure-activity studies identified a number of promising compounds with selective antiplasmodial activity. One of these frontrunner compounds, 15, was equipotent across the two strains (K1 = 25.0 nM, NF54 = 28.0 nM) and superior to chloroquine in the K1 strain (chloroquine IC(50) K1 = 194.0 nM). Compound 15 completely cured Plasmodium berghei-infected mice with a single oral dose of 30 mg/kg. Dose-response studies generated ED(50) and ED(90) values of 0.83 and 1.74 mg/kg for 15 in the standard four-dose Peters test. Pharmacokinetic studies in the rat indicated that this compound has good oral bioavailability (51% at 20 mg/kg) and a reasonable half-life (t(1/2) ∼ 7-8 h)., (© 2012 American Chemical Society)
- Published
- 2012
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- View/download PDF
22. Proton-detected solid-state NMR reveals intramembrane polar networks in a seven-helical transmembrane protein proteorhodopsin.
- Author
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Ward ME, Shi L, Lake E, Krishnamurthy S, Hutchins H, Brown LS, and Ladizhansky V
- Subjects
- Models, Molecular, Nuclear Magnetic Resonance, Biomolecular, Rhodopsin isolation & purification, Rhodopsins, Microbial, Protons, Rhodopsin chemistry
- Abstract
We used high-resolution proton-detected multidimensional NMR to study the solvent-exposed parts of a seven-helical integral membrane proton pump, proteorhodopsin (PR). PR samples were prepared by growing the apoprotein on fully deuterated medium and reintroducing protons to solvent-accessible sites through exchange with protonated buffer. This preparation leads to NMR spectra with proton resolution down to ca. 0.2 ppm at fast spinning (28 kHz) in a protein back-exchanged at a level of 40%. Novel three-dimensional proton-detected chemical shift correlation spectroscopy allowed for the identification and resonance assignment of the solvent-exposed parts of the protein. Most of the observed residues are located at the membrane interface, but there are notable exceptions, particularly in helix G, where most of the residues are susceptible to H/D exchange. This helix contains Schiff base-forming Lys231, and many conserved polar residues in the extracellular half, such as Asn220, Tyr223, Asn224, Asp227, and Asn230. We proposed earlier that high mobility of the F-G loop may transiently expose a hydrophilic cavity in the extracellular half of the protein, similar to the one found in xanthorhodopsin. Solvent accessibility of helix G is in line with this hypothesis, implying that such a cavity may be a part of the proton-conducting pathway lined by this helix.
- Published
- 2011
- Full Text
- View/download PDF
23. Display of solid-state materials using bipolar electrochemistry.
- Author
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Ramakrishnan S and Shannon C
- Abstract
We report the formation and characterization of one-dimensional chemical composition gradients of CdS on Au surfaces using bipolar electrodeposition. When an external electric field is applied across an electrically floating Au electrode immersed in a bipolar electrochemical cell, a position-dependent interfacial potential difference is generated along the length of the Au. This potential gradient can be used to induce variations of chemical composition within thin films electrodeposited onto the Au bipolar electrode (BPE). Thin films formed by bipolar electrodeposition represent continuous one-dimensional solid-state material libraries and were screened using resonance Raman microscopy and Auger electron spectroscopy. As predicted from simple thermodynamic considerations, we observed three distinct deposition zones scanning from the cathodic pole to the midpoint of the BPE: (i) CdS+Cd, (ii) stoichiometric CdS, and (iii) elemental S. Bipolar electrodeposition can be used to generate material libraries rapidly and without direct electrical contact to the substrate using extremely simple instrumentation.
- Published
- 2010
- Full Text
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24. Protection against aflatoxin B1-induced cytotoxicity by expression of the cloned aflatoxin B1-aldehyde reductases rat AKR7A1 and human AKR7A3.
- Author
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Bodreddigari S, Jones LK, Egner PA, Groopman JD, Sutter CH, Roebuck BD, Guengerich FP, Kensler TW, and Sutter TR
- Subjects
- Aflatoxin B1 chemistry, Aldehyde Reductase genetics, Animals, Cell Line, Chlorocebus aethiops, Humans, Liver drug effects, Liver enzymology, Molecular Structure, RNA, Messenger genetics, Rats, Aflatoxin B1 toxicity, Aldehyde Reductase metabolism, Gene Expression Regulation, Enzymologic drug effects
- Abstract
The reduction of the aflatoxin B 1 (AFB 1) dialdehyde metabolite to its corresponding mono and dialcohols, catalyzed by aflatoxin B 1-aldehyde reductase (AFAR, rat AKR7A1, and human AKR7A3), is greatly increased in livers of rats treated with numerous chemoprotective agents. Recombinant human AKR7A3 has been shown to reduce the AFB 1-dialdehyde at rates greater than those of the rat AKR7A1. The activity of AKR7A1 or AKR7A3 may detoxify the AFB 1-dialdehyde, which reacts with proteins, and thereby inhibits AFB 1-induced toxicity; however, direct experimental evidence of this hypothesis was lacking. Two human B lymphoblastoid cell lines, designated pMF6/1A2/AKR7A1 and pMF6/1A2, were genetically engineered to stably express AKR7A1 and/or cytochrome P4501A2 (1A2). The pMF6/1A2/AKR7A1 cells were refractory to the cytotoxic effects of 3 ng/mL AFB 1, in comparison to pM6/1A2 cells, which were more sensitive. Diminished protection occurred at higher concentrations of AFB 1 in pMF6/1A2/AKR7A1 cells, suggesting that additional factors were influencing cell survival. COS-7 cells were transfected with either vector control, rat AKR7A1, or human AKR7A3, and the cells were treated with AFB 1-dialdehyde. There was a 6-fold increase in the dialdehyde LC 50, from 66 microM in vector-transfected cells to 400 microM in AKR7A1-transfected cells, and an 8.5-fold increase from 35 microM in vector-transfected cells to 300 microM in AKR7A3-transfected cells. In both cases, this protective effect of the AFAR enzyme was accompanied by a marked decrease in protein adducts. Fractionation of the cellular protein showed that the mitochondria/nuclei and microsomal fractions contained the highest concentration of protein adducts. The levels of human AKR7A3 and AKR7A2 were measured in 12 human liver samples. The expression of AKR7A3 was detectable in all livers and lower than those of AKR7A2 in 11 of the 12 samples. Overall, these results provide the first direct evidence of a role for rat AKR7A1 and human AKR7A3 in protection against AFB 1-induced cytotoxicity and protein adduct formation.
- Published
- 2008
- Full Text
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25. Improved oxygen reduction cathodes using polyoxometalate cocatalysts.
- Author
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Sankarraj AV, Ramakrishnan S, and Shannon C
- Abstract
We report on the influence of a series of transition-metal-substituted Wells-Dawson (P2W17MnO62(12-n)-; M = WVI, FeII, CoII, RuII) and Keggin (PW12O40(3-) and PCoW11O39(5-) anions on the oxygen reduction reaction (ORR) at Au, Pd, and Pt. Wells-Dawson POMs adsorbed on Au lead to large positive shifts of the ORR potential. The magnitude of the shift depends on the transition metal and is explained using a simple thermodynamic model. The best cathode performance was achieved using a PCoW11O39(5-) cocatalyst and a Pt cathode. The +54 mV positive shift in the ORR potential that we observed is comparable to the performance of the best-known bimetallic catalysts.
- Published
- 2008
- Full Text
- View/download PDF
26. Synergistic use of compound properties and docking scores in neural network modeling of CYP2D6 binding: predicting affinity and conformational sampling.
- Author
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Bazeley PS, Prithivi S, Struble CA, Povinelli RJ, and Sem DS
- Subjects
- Algorithms, Binding Sites, Drug Design, Humans, Ligands, Models, Molecular, Molecular Conformation, Neural Networks, Computer, Protein Binding, Protein Conformation, Software, Chemistry, Pharmaceutical methods, Cytochrome P-450 CYP2D6 chemistry, Drug Synergism, Technology, Pharmaceutical methods
- Abstract
Cytochrome P450 2D6 (CYP2D6) is used to develop an approach for predicting affinity and relevant binding conformation(s) for highly flexible binding sites. The approach combines the use of docking scores and compound properties as attributes in building a neural network (NN) model. It begins by identifying segments of CYP2D6 that are important for binding specificity, based on structural variability among diverse CYP enzymes. A family of distinct, low-energy conformations of CYP2D6 are generated using simulated annealing (SA) and a collection of 82 compounds with known CYP2D6 affinities are docked. Interestingly, docking poses are observed on the backside of the heme as well as in the known active site. Docking scores for the active site binders, along with compound-specific attributes, are used to train a neural network model to properly bin compounds as strong binders, moderate binders, or nonbinders. Attribute selection is used to preselect the most important scores and compound-specific attributes for the model. A prediction accuracy of 85+/-6% is achieved. Dominant attributes include docking scores for three of the 20 conformations in the ensemble as well as the compound's formal charge, number of aromatic rings, and AlogP. Although compound properties were highly predictive attributes (12% improvement over baseline) in the NN-based prediction of CYP2D6 binders, their combined use with docking score attributes is synergistic (net increase of 23% above baseline). Beyond prediction of affinity, attribute selection provides a way to identify the most relevant protein conformation(s), in terms of binding competence. In the case of CYP2D6, three out of the ensemble of 20 SA-generated structures are found to be the most predictive for binding.
- Published
- 2006
- Full Text
- View/download PDF
27. Telomestatin and diseleno sapphyrin bind selectively to two different forms of the human telomeric G-quadruplex structure.
- Author
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Rezler EM, Seenisamy J, Bashyam S, Kim MY, White E, Wilson WD, and Hurley LH
- Subjects
- Binding Sites, Circular Dichroism, DNA chemistry, G-Quadruplexes, Humans, Ligands, Molecular Structure, Oligonucleotides chemistry, Oligonucleotides metabolism, Oncogene Proteins chemistry, Oncogene Proteins metabolism, Oxazoles chemistry, Polymerase Chain Reaction, Porphyrins chemistry, Potassium pharmacology, Selenium Compounds chemistry, Sodium pharmacology, Substrate Specificity, Surface Plasmon Resonance, Telomere chemistry, DNA metabolism, Oxazoles metabolism, Porphyrins metabolism, Selenium Compounds metabolism, Telomere metabolism
- Abstract
The human telomeric sequence d[T(2)AG(3)](4) has been demonstrated to form different types of G-quadruplex structures, depending upon the incubation conditions. For example, in sodium (Na(+)), a basket-type G-quadruplex structure is formed. In this investigation, using circular dichroism (CD), biosensor-surface plasmon resonance (SPR), and a polymerase stop assay, we have examined how the addition of different G-quadruplex-binding ligands affects the conformation of the telomeric G-quadruplex found in solution. The results show that while telomestatin binds preferentially to the basket-type G-quadruplex structure with a 2:1 stoichiometry, 5,10,15,20-[tetra-(N-methyl-3-pyridyl)]-26-28-diselena sapphyrin chloride (Se2SAP) binds to a different form with a 1:1 stoichiometry in potassium (K(+)). CD studies suggest that Se2SAP binds to a hybrid G-quadruplex that has strong parallel and antiparallel characteristics, suggestive of a structure containing both propeller and lateral, or edgewise, loops. Telomestatin is unique in that it can induce the formation of the basket-type G-quadruplex from a random coil human telomeric oligonucleotide, even in the absence of added monovalent cations such as K(+) or Na(+). In contrast, in the presence of K(+), Se2SAP was found to convert the preformed basket G-quadruplex to the hybrid structure. The significance of these results is that the presence of different ligands can determine the type of telomeric G-quadruplex structures formed in solution. Thus, the biochemical and biological consequences of binding of ligands to G-quadruplex structures found in telomeres and promoter regions of certain important oncogenes go beyond mere stabilization of these structures.
- Published
- 2005
- Full Text
- View/download PDF
28. Design and synthesis of an expanded porphyrin that has selectivity for the c-MYC G-quadruplex structure.
- Author
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Seenisamy J, Bashyam S, Gokhale V, Vankayalapati H, Sun D, Siddiqui-Jain A, Streiner N, Shin-Ya K, White E, Wilson WD, and Hurley LH
- Subjects
- Binding, Competitive, DNA chemistry, DNA genetics, DNA, Single-Stranded chemistry, DNA, Single-Stranded metabolism, G-Quadruplexes, Guanine metabolism, HeLa Cells, Humans, Models, Molecular, Nucleic Acid Conformation drug effects, Oxazoles chemistry, Oxazoles metabolism, Oxazoles pharmacology, Porphyrins chemistry, Porphyrins metabolism, Porphyrins pharmacology, Promoter Regions, Genetic, Selenium Compounds chemistry, Selenium Compounds metabolism, Selenium Compounds pharmacology, Substrate Specificity, Surface Plasmon Resonance, Telomere chemistry, Telomere metabolism, DNA metabolism, Genes, myc, Porphyrins chemical synthesis, Selenium Compounds chemical synthesis
- Abstract
Cationic porphyrins are known to bind to and stabilize different types of G-quadruplexes. Recent studies have shown the biological relevance of the intramolecular parallel G-quadruplex as a transcriptional silencer in the c-MYC promoter. TMPyP4 also binds to this G-quadruplex and most likely converts it to a mixed parallel/antiparallel G-quadruplex with two external lateral loops and one internal propeller loop, suppressing c-MYC transcriptional activation. To achieve therapeutic selectivity by targeting G-quadruplexes, it is necessary to synthesize drugs that can differentiate among the different types of G-quadruplexes. We have designed and synthesized a core-modified expanded porphyrin analogue, 5,10,15,20-[tetra(N-methyl-3-pyridyl)]-26,28-diselenasapphyrin chloride (Se2SAP). Se2SAP converts the parallel c-MYC G-quadruplex into a mixed parallel/antiparallel G-quadruplex with one external lateral loop and two internal propeller loops, resulting in strong and selective binding to this G-quadruplex. A Taq polymerase stop assay was used to evaluate the binding of TMPyP4 and Se2SAP to G-quadruplex DNA. Compared to TMPyP4, Se2SAP shows a greater selectivity for and a 40-fold increase in stabilization of the single lateral-loop hybrid. Surface plasmon resonance and competition experiments with duplex DNA and other G-quadruplexes further confirmed the selectivity of Se2SAP for the c-MYC G-quadruplex. Significantly, Se2SAP was found to be less photoactive and noncytotoxic in comparison to TMPyP4. From this study, we have identified an expanded porphyrin that selectively binds with the c-MYC G-quadruplex in the presence of duplex DNA and other G-quadruplexes.
- Published
- 2005
- Full Text
- View/download PDF
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