The Experts below are selected from a list of 180024 Experts worldwide ranked by ideXlab platform
Vicky M Avery - One of the best experts on this subject based on the ideXlab platform.
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a luciferase based viability assay for atp detection in 384 well format for high throughput whole Cell Screening of trypanosoma brucei brucei bloodstream form strain 427
Parasites & Vectors, 2009Co-Authors: Melissa Sykes, Vicky M AveryAbstract:Background Human African Trypanosomiasis (HAT) is caused by two trypanosome species, Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. Current drugs available for the treatment of HAT have significant issues related to toxicity, administration regimes with limited effectiveness across species and disease stages, thus there is a considerable need to find alternative drugs. A well recognised approach to identify new drug candidates is high throughput Screening (HTS) of large compound library collections.
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development of an alamar blue viability assay in 384 well format for high throughput whole Cell Screening of trypanosoma brucei brucei bloodstream form strain 427
American Journal of Tropical Medicine and Hygiene, 2009Co-Authors: Melissa Sykes, Vicky M AveryAbstract:1T. b. rhodesiense is mainly prevalent in eastern and southern Africa and T. b.gambiense is predominantly in western and central Africa. The disease has two distinct stages. The first stage has few, if any specific symptoms. The second stage, once the parasites have crossed the blood-brain barrier, causes severe neurologic symptoms and eventually a somnolescent state, giving the disease its name. Ultimately, if left untreated, the disease is fatal. Few advances have been made in the treatment of HAT and most of the current drugs available were discovered before the 1950s. 2
Courtney C Aldrich - One of the best experts on this subject based on the ideXlab platform.
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structure based optimization of pyridoxal 5 phosphate dependent transaminase enzyme bioa inhibitors that target biotin biosynthesis in mycobacterium tuberculosis
Journal of Medicinal Chemistry, 2017Co-Authors: Feng Liu, Surendra Dawadi, Kimberly M Maize, Ran Dai, Sae Woong Park, Dirk Schnappinger, Barry C Finzel, Courtney C AldrichAbstract:The pyridoxal 5′-phosphate (PLP)-dependent transaminase BioA catalyzes the second step in the biosynthesis of biotin in Mycobacterium tuberculosis (Mtb) and is an essential enzyme for bacterial survival and persistence in vivo. A promising BioA inhibitor 6 containing an N-aryl, N′-benzoylpiperazine scaffold was previously identified by target-based whole-Cell Screening. Here, we explore the structure–activity relationships (SAR) through the design, synthesis, and biological evaluation of a systematic series of analogues of the original hit using a structure-based drug design strategy, which was enabled by cocrystallization of several analogues with BioA. To confirm target engagement and discern analogues with off-target activity, each compound was evaluated against wild-type (WT) Mtb in biotin-free and -containing medium as well as BioA under- and overexpressing Mtb strains. Conformationally constrained derivative 36 emerged as the most potent analogue with a KD of 76 nM against BioA and a minimum inhibit...
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Structure-Based Optimization of Pyridoxal 5′-Phosphate-Dependent Transaminase Enzyme (BioA) Inhibitors that Target Biotin Biosynthesis in Mycobacterium tuberculosis
2017Co-Authors: Feng Liu, Surendra Dawadi, Kimberly M Maize, Ran Dai, Sae Woong Park, Dirk Schnappinger, Barry C Finzel, Courtney C AldrichAbstract:The pyridoxal 5′-phosphate (PLP)-dependent transaminase BioA catalyzes the second step in the biosynthesis of biotin in Mycobacterium tuberculosis (Mtb) and is an essential enzyme for bacterial survival and persistence in vivo. A promising BioA inhibitor 6 containing an N-aryl, N′-benzoylpiperazine scaffold was previously identified by target-based whole-Cell Screening. Here, we explore the structure–activity relationships (SAR) through the design, synthesis, and biological evaluation of a systematic series of analogues of the original hit using a structure-based drug design strategy, which was enabled by cocrystallization of several analogues with BioA. To confirm target engagement and discern analogues with off-target activity, each compound was evaluated against wild-type (WT) Mtb in biotin-free and -containing medium as well as BioA under- and overexpressing Mtb strains. Conformationally constrained derivative 36 emerged as the most potent analogue with a KD of 76 nM against BioA and a minimum inhibitory concentration of 1.7 μM (0.6 μg/mL) against Mtb in biotin-free medium
Melissa Sykes - One of the best experts on this subject based on the ideXlab platform.
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a luciferase based viability assay for atp detection in 384 well format for high throughput whole Cell Screening of trypanosoma brucei brucei bloodstream form strain 427
Parasites & Vectors, 2009Co-Authors: Melissa Sykes, Vicky M AveryAbstract:Background Human African Trypanosomiasis (HAT) is caused by two trypanosome species, Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. Current drugs available for the treatment of HAT have significant issues related to toxicity, administration regimes with limited effectiveness across species and disease stages, thus there is a considerable need to find alternative drugs. A well recognised approach to identify new drug candidates is high throughput Screening (HTS) of large compound library collections.
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development of an alamar blue viability assay in 384 well format for high throughput whole Cell Screening of trypanosoma brucei brucei bloodstream form strain 427
American Journal of Tropical Medicine and Hygiene, 2009Co-Authors: Melissa Sykes, Vicky M AveryAbstract:1T. b. rhodesiense is mainly prevalent in eastern and southern Africa and T. b.gambiense is predominantly in western and central Africa. The disease has two distinct stages. The first stage has few, if any specific symptoms. The second stage, once the parasites have crossed the blood-brain barrier, causes severe neurologic symptoms and eventually a somnolescent state, giving the disease its name. Ultimately, if left untreated, the disease is fatal. Few advances have been made in the treatment of HAT and most of the current drugs available were discovered before the 1950s. 2
M P Rubtsova - One of the best experts on this subject based on the ideXlab platform.
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microfluidic droplet platform for ultrahigh throughput single Cell Screening of biodiversity
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: S S Terekhov, I V Smirnov, A V Stepanova, T V Bobik, Yuliana A Mokrushina, Natalia A Ponomarenko, A A Belogurov, M P RubtsovaAbstract:Ultrahigh-throughput Screening (uHTS) techniques can identify unique functionality from millions of variants. To mimic the natural selection mechanisms that occur by compartmentalization in vivo, we developed a technique based on single-Cell encapsulation in droplets of a monodisperse microfluidic double water-in-oil-in-water emulsion (MDE). Biocompatible MDE enables in-droplet cultivation of different living species. The combination of droplet-generating machinery with FACS followed by next-generation sequencing and liquid chromatography-mass spectrometry analysis of the secretomes of encapsulated organisms yielded detailed genotype/phenotype descriptions. This platform was probed with uHTS for biocatalysts anchored to yeast with enrichment close to the theoretically calculated limit and Cell-to-Cell interactions. MDE-FACS allowed the identification of human butyrylcholinesterase mutants that undergo self-reactivation after inhibition by the organophosphorus agent paraoxon. The versatility of the platform allowed the identification of bacteria, including slow-growing oral microbiota species that suppress the growth of a common pathogen, Staphylococcus aureus, and predicted which genera were associated with inhibitory activity.
Feng Liu - One of the best experts on this subject based on the ideXlab platform.
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structure based optimization of pyridoxal 5 phosphate dependent transaminase enzyme bioa inhibitors that target biotin biosynthesis in mycobacterium tuberculosis
Journal of Medicinal Chemistry, 2017Co-Authors: Feng Liu, Surendra Dawadi, Kimberly M Maize, Ran Dai, Sae Woong Park, Dirk Schnappinger, Barry C Finzel, Courtney C AldrichAbstract:The pyridoxal 5′-phosphate (PLP)-dependent transaminase BioA catalyzes the second step in the biosynthesis of biotin in Mycobacterium tuberculosis (Mtb) and is an essential enzyme for bacterial survival and persistence in vivo. A promising BioA inhibitor 6 containing an N-aryl, N′-benzoylpiperazine scaffold was previously identified by target-based whole-Cell Screening. Here, we explore the structure–activity relationships (SAR) through the design, synthesis, and biological evaluation of a systematic series of analogues of the original hit using a structure-based drug design strategy, which was enabled by cocrystallization of several analogues with BioA. To confirm target engagement and discern analogues with off-target activity, each compound was evaluated against wild-type (WT) Mtb in biotin-free and -containing medium as well as BioA under- and overexpressing Mtb strains. Conformationally constrained derivative 36 emerged as the most potent analogue with a KD of 76 nM against BioA and a minimum inhibit...
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Structure-Based Optimization of Pyridoxal 5′-Phosphate-Dependent Transaminase Enzyme (BioA) Inhibitors that Target Biotin Biosynthesis in Mycobacterium tuberculosis
2017Co-Authors: Feng Liu, Surendra Dawadi, Kimberly M Maize, Ran Dai, Sae Woong Park, Dirk Schnappinger, Barry C Finzel, Courtney C AldrichAbstract:The pyridoxal 5′-phosphate (PLP)-dependent transaminase BioA catalyzes the second step in the biosynthesis of biotin in Mycobacterium tuberculosis (Mtb) and is an essential enzyme for bacterial survival and persistence in vivo. A promising BioA inhibitor 6 containing an N-aryl, N′-benzoylpiperazine scaffold was previously identified by target-based whole-Cell Screening. Here, we explore the structure–activity relationships (SAR) through the design, synthesis, and biological evaluation of a systematic series of analogues of the original hit using a structure-based drug design strategy, which was enabled by cocrystallization of several analogues with BioA. To confirm target engagement and discern analogues with off-target activity, each compound was evaluated against wild-type (WT) Mtb in biotin-free and -containing medium as well as BioA under- and overexpressing Mtb strains. Conformationally constrained derivative 36 emerged as the most potent analogue with a KD of 76 nM against BioA and a minimum inhibitory concentration of 1.7 μM (0.6 μg/mL) against Mtb in biotin-free medium