The Experts below are selected from a list of 213 Experts worldwide ranked by ideXlab platform
Seok-yong Lee - One of the best experts on this subject based on the ideXlab platform.
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Structural basis of nucleoside and nucleoside Drug Selectivity by concentrative nucleoside transporters
eLife, 2014Co-Authors: Zachary Lee Johnson, Jun Ho Lee, Kiyoun Lee, Minhee Lee, Do-yeon Kwon, Jiyong Hong, Seok-yong LeeAbstract:DNA molecules are made from four bases—often named ‘G’, ‘A’, ‘C’, and ‘T’—that are arranged along a backbone made of sugars and phosphate groups. Chemicals called nucleosides are essentially the same as these four building blocks of DNA (and other similar molecules) but without the phosphate groups. Proteins called nucleoside transporters are found in the membranes that surround cells and can pump nucleosides into the cell. These transporters also allow Drugs that are made from modified nucleosides to enter cells; however, it was previously unclear how different transporters recognized and imported specific nucleosides. Like other proteins, nucleoside transporters are basically strings of amino acids that have folded into a specific three-dimensional shape. A protein's shape is often important for defining what that protein can do, as often other molecules must bind to proteins—much like a key fitting into a lock. Johnson et al. have now revealed the three-dimensional structure of one nucleoside transporter protein bound to different nucleosides and nucleoside-derived chemicals, including three anti-cancer Drugs and one anti-viral Drug. Some of these chemicals were shown to bind more strongly to the transporter protein than others, and examining the three-dimensional structures revealed that the different chemicals interacted with slightly different amino acids in the transporter protein. Johnson et al. then used this information to chemically modify an anticancer Drug so that it is transported more easily into cells and is imported by only one of the subtypes of nucleoside transporters that are found in humans. This provides proof of principle that information about the structure and function of a transporter protein can help to redesign chemicals such that they can enter cells more efficiently, and to tailor them for transport by specific transporters. A similar approach may in the future allow researchers to design new nucleoside-derived Drugs that are better at getting inside specific cells and, as such, provide effective treatments against cancers and viral infections.
Weilin L Shelver - One of the best experts on this subject based on the ideXlab platform.
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validation of the betastar advanced for tetracyclines test kit for the screening of bulk tank and tanker truck milks for the presence of tetracycline Drug residues
Journal of AOAC International, 2018Co-Authors: David Ankrapp, Benjamin Schaus, Lauren Clements, Frank Klein, Jennifer Rice, John J Rejman, Joe O Boison, Philip Kijak, Weilin L ShelverAbstract:A validation study was conducted for an immunochromatographic method (BetaStar® Advanced for Tetracyclines) for detection of tetracycline antibiotic residues in raw, commingled bovine milk. The assay was demonstrated to detect tetracycline, chlortetracycline, and oxytetracycline at levels below the FDA tolerance levels but above the maximum sensitivity thresholds established by the National Conference on Interstate Milk Shipments. Results of internal and independent laboratory dose-response studies employing spiked samples were in agreement. All three Drugs at the approximate 90/95% sensitivity levels were detected in milk collected from cows that had been treated with the specific Drug. Selectivity of the assay was 100%, as no false-positive results were obtained in testing 881 control milk samples. Testing the estimated 90/95 sensitivity level for tetracycline (213 ppb), chlortetracycline (272 ppb), and oxytetracycline (180 ppb) and at 1000 ppb for each antibiotic resulted in 100% positive tests for each tetracycline. Results of ruggedness experiments established the operating parameter tolerances for the test. Results of cross-reactivity testing established that the assay detects certain other tetracycline Drugs but does not cross-react with any of 32 Drugs belonging to seven different Drug classes. Abnormally high bacterial or somatic cell counts (SCC) in raw milk produced no assay interference.
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validation of the betastar advanced for beta lactams test kit for the screening of bulk tank and tanker truck milks for the presence of beta lactam Drug residues
Journal of AOAC International, 2018Co-Authors: Andrew John Denhartigh, Frank Klein, Jennifer Rice, John J Rejman, Joe O Boison, Philip Kijak, Lindsay Reynolds, Katherine Palmer, Weilin L ShelverAbstract:A validation study was conducted for an immunochromatographic method (BetaStar® Advanced for Beta-lactams) for the detection of beta-lactam residues in raw, commingled bovine milk. The assay detected amoxicillin, ampicillin, cloxacillin, penicillin, cephapirin, and ceftiofur below the U.S. Food and Drug Administration tolerance levels but above the maximum sensitivity thresholds established by the National Conference on Interstate Milk Shipments. The results of internal and independent laboratory dose-response studies employing spiked samples were in agreement. The test detected all six Drugs at the approximate 90/95% sensitivity levels in milk from cows treated with each Drug. Selectivity of the assay was 100%, as no false-positive results were obtained in testing 1148 control milk samples. Testing the estimated 90/95% sensitivity level for amoxicillin (8.5 ppb), ampicillin (6.9 ppb), cloxacillin (8.9 ppb), penicillin (4.2 ppb), and cephapirin (17.6 ppb), and at 100 ppb for each antibiotic, resulted in 94-100% positive tests for each of the beta-lactam Drugs. The results of ruggedness experiments established the operating parameter tolerances for the assay. Cross-reactivity testing established that the assay detects other certain beta-lactam Drugs, but it does not cross-react with any of 30 Drugs belonging to seven different Drug classes. Abnormally high bacterial or somatic cell counts in raw milk produced no assay interference.
N J M Birdsall - One of the best experts on this subject based on the ideXlab platform.
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subtype selective positive cooperative interactions between brucine analogues and acetylcholine at muscarinic receptors radioligand binding studies
Molecular Pharmacology, 1998Co-Authors: Sebastian Lazareno, Parviz Gharagozloo, D Kuonen, A Popham, N J M BirdsallAbstract:We studied the interactions of strychnine, brucine, and three of the N-substituted analogues of brucine with [3H]N-methylscopolamine (NMS) and unlabeled acetylcholine at m1-m5 muscarinic receptors using equilibrium and nonequilibrium radioligand binding studies. The results were consistent with a ternary allosteric model in which both the primary and allosteric ligands bind simultaneously to the receptor and modify the affinities of each other. The compounds had Kd values in the submillimolar range, inhibited [3H]NMS dissociation, and showed various patterns of positive, neutral, and negative cooperativity with [3H]NMS and acetylcholine, but there was no predictive relationship between the effects. Acetylcholine affinity was increased approximately 2-fold by brucine at m1 receptors, approximately 3-fold by N-chloromethyl brucine at m3 receptors, and approximately 1.5-fold by brucine-N-oxide at m4 receptors. The existence of neutral cooperativity, in which the compound bound to the receptor but did not modify the affinity of acetylcholine, provides the opportunity for a novel form of Drug Selectivity that we refer to as absolute subtype Selectivity: an agent showing positive or negative cooperativity with the endogenous ligand at one receptor subtype and neutral cooperativity at the other subtypes would exert functional effects at only the one subtype, regardless of the concentration of agent or its affinities for the subtypes. Our results demonstrate the potential for developing allosteric enhancers of acetylcholine affinity at individual subtypes of muscarinic receptor and suggest that minor modification of a compound showing positive, neutral, or low negative cooperativity with acetylcholine may yield compounds with various patterns of cooperativity across the receptor subtypes.
Bernhard Kuster - One of the best experts on this subject based on the ideXlab platform.
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comparing immobilized kinase inhibitors and covalent atp probes for proteomic profiling of kinase expression and Drug Selectivity
Journal of Proteome Research, 2013Co-Authors: Simone Lemeer, Corina Zorgiebel, Benjamin Ruprecht, Kristian Kohl, Bernhard KusterAbstract:Kinases are involved in the regulation of many cellular processes and aberrant kinase signaling has been implicated in human disease. As a consequence, kinases are attractive Drug targets. Assessing kinase function and Drug Selectivity in a more physiological context is challenging and often hampered by the generally low expression level of kinases and the extensive post-translation modification in vivo. Kinase Drug Selectivity screens by chemical proteomics have gained attention because they allow the profiling of hundreds of kinases against one Drug at the same time. Here, we directly compared two such methods, notably, immobilized broad spectrum kinase inhibitors (kinobeads) and active site labeling using desthiobiotin-ATP and -ADP probes. Affinity purification of ∼100 kinases by either kinobeads or ATP/ADP probes was readily achieved using 1 mg of cellular protein. Bioinformatic analysis revealed a high degree of complementarity of the two techniques. Kinobeads covered the Tyrosine Kinase family parti...
Zachary Lee Johnson - One of the best experts on this subject based on the ideXlab platform.
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Structural basis of nucleoside and nucleoside Drug Selectivity by concentrative nucleoside transporters
eLife, 2014Co-Authors: Zachary Lee Johnson, Jun Ho Lee, Kiyoun Lee, Minhee Lee, Do-yeon Kwon, Jiyong Hong, Seok-yong LeeAbstract:DNA molecules are made from four bases—often named ‘G’, ‘A’, ‘C’, and ‘T’—that are arranged along a backbone made of sugars and phosphate groups. Chemicals called nucleosides are essentially the same as these four building blocks of DNA (and other similar molecules) but without the phosphate groups. Proteins called nucleoside transporters are found in the membranes that surround cells and can pump nucleosides into the cell. These transporters also allow Drugs that are made from modified nucleosides to enter cells; however, it was previously unclear how different transporters recognized and imported specific nucleosides. Like other proteins, nucleoside transporters are basically strings of amino acids that have folded into a specific three-dimensional shape. A protein's shape is often important for defining what that protein can do, as often other molecules must bind to proteins—much like a key fitting into a lock. Johnson et al. have now revealed the three-dimensional structure of one nucleoside transporter protein bound to different nucleosides and nucleoside-derived chemicals, including three anti-cancer Drugs and one anti-viral Drug. Some of these chemicals were shown to bind more strongly to the transporter protein than others, and examining the three-dimensional structures revealed that the different chemicals interacted with slightly different amino acids in the transporter protein. Johnson et al. then used this information to chemically modify an anticancer Drug so that it is transported more easily into cells and is imported by only one of the subtypes of nucleoside transporters that are found in humans. This provides proof of principle that information about the structure and function of a transporter protein can help to redesign chemicals such that they can enter cells more efficiently, and to tailor them for transport by specific transporters. A similar approach may in the future allow researchers to design new nucleoside-derived Drugs that are better at getting inside specific cells and, as such, provide effective treatments against cancers and viral infections.
