The Experts below are selected from a list of 6240747 Experts worldwide ranked by ideXlab platform
Savvas N. Savvides - One of the best experts on this subject based on the ideXlab platform.
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Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors
Journal of Medicinal Chemistry, 2018Co-Authors: Lijun Song, Hélène Munier-lehmann, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Begoña Gracia, Ainhoa Lucía Quintana, Paul Cos, José A. Aínsa, Savvas N. SavvidesAbstract:In recent years, thymidylate kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK ( MtTMPK) Inhibitors, and reported here the design of a novel series of non-nucleoside Inhibitors of MtTMPK. The Inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure-activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump Inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular Inhibitors increased significantly when determined for the efflux pump mmr knockout mutant, which partly explains the observed dissonance
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Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors
Journal of medicinal chemistry, 2018Co-Authors: Lijun Song, Hélène Munier-lehmann, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Begoña Gracia, Ainhoa Lucía Quintana, Paul Cos, José A. Aínsa, Savvas N. SavvidesAbstract:In recent years, thymidylate kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK (MtTMPK) Inhibitors, and reported here the design of a novel series of non-nucleoside Inhibitors of MtTMPK. The Inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure–activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump Inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular Inhibitors increased significantly when determined for the eff...
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Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors
2018Co-Authors: Lijun Song, Hélène Munier-lehmann, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Paul Cos, Begoña Gracia, Ainhoa Lucía Quintana, José A. Aínsa, Savvas N. SavvidesAbstract:In recent years, thymidylate kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK (MtTMPK) Inhibitors, and reported here the design of a novel series of non-nucleoside Inhibitors of MtTMPK. The Inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure–activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump Inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular Inhibitors increased significantly when determined for the efflux pump mmr knockout mutant, which partly explains the observed dissonance
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The design and synthesis of Inhibitors of Mycobacterium tuberculosis thymidylate kinase (MtTMPK)
2016Co-Authors: Lijun Song, Hélène Munier-lehmann, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Savvas N. Savvides, Serge Van CalenberghAbstract:Thymidylate kinase (TMPK) phosphorylates thymidine 5’-monophosphate (dTMP) to thymidine 5’-diphosphate (dTDP) and has been proposed as an attractive anti-tubercular target. By mimicking the structure of the substrate (dTMP), we have previously discovered different series of nucleoside analogues with Mycobacterium tuberculosis (Mt) TMPK inhibitory activities in the micromolar range. Based on recently reported potent piperidin-3-yl-thymine Inhibitors of Gram-positive bacterial TMPK, we report a series of isomeric N-benzyl-substituted piperidin-4-yl-thymine analogues, some of which demonstrate very promising MtTMPK inhibitory potency. This poster will discuss the synthesis, MtTMPK inhibitory activity, as well as structural data on how these new Inhibitors interact with the target enzyme.
Mrinmoy Nag - One of the best experts on this subject based on the ideXlab platform.
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tyrosinase inhibitory potential of purpurin in rubia cordifolia a bioactivity guided approach
Industrial Crops and Products, 2015Co-Authors: Rajarshi Biswas, Pulok K. Mukherjee, Manoj Kumar Dalai, Prasanta Mandal, Mrinmoy NagAbstract:Abstract The Rubia cordifolia Linn (Manjistha) is a wealthy resource of anthraquinones and its derivatives. In this study, the tyrosinase inhibitory potential of R. cordifolia (root extracts) was explored through bio-activity guided fractionation. Anti-tyrosinase assay guided fractionation led to obtained three different bioactive fractions, e.g ., F3, F4 and F5 from plant extract. Subsequent, Liquid chromatographic (RP-HPLC) analysis revealed the active fractions contained 0.89 ± 0.03%, 3.24 ± 0.18% and 2.03 ± 0.24% (w/w) of purpurin respectively. The study indicated that the most bioactive fraction of R. cordifolia (F4) and purpurin showed primarily monophenolase inhibition and to a lesser extent diphenolase inhibitory activity. In addition, results of enzyme kinetic analysis shown F4 and purpurin reversibly inhibited tyrosinase in a competitive manner. 1-Anilino-8-naphthalene sulfonate (ANS)-binding fluorescence measurement proved that conformation of tertiary structure of tyrosinase was not altered by Inhibitors. Although circular dichroism (CD) spectroscopy analysis showed that α-helical content of secondary structure decreased with increment of inhibitor's concentration. Molecular docking results implied that the possible inhibitory mechanisms may be attributed to purpurin interaction with copper ion coordinating three histidine residues (HIS61, HIS85, and HIS263) of tyrosinase. This finding could be of importance in prevention of the undesirable enzymatic browning reaction of food products, as well as hyper-pigmentation of human skin.
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Tyrosinase inhibitory potential of purpurin in Rubia cordifolia—A bioactivity guided approach
Industrial Crops and Products, 2015Co-Authors: Rajarshi Biswas, Pulok K. Mukherjee, Manoj Kumar Dalai, Prasanta Mandal, Mrinmoy NagAbstract:Abstract The Rubia cordifolia Linn (Manjistha) is a wealthy resource of anthraquinones and its derivatives. In this study, the tyrosinase inhibitory potential of R. cordifolia (root extracts) was explored through bio-activity guided fractionation. Anti-tyrosinase assay guided fractionation led to obtained three different bioactive fractions, e.g ., F3, F4 and F5 from plant extract. Subsequent, Liquid chromatographic (RP-HPLC) analysis revealed the active fractions contained 0.89 ± 0.03%, 3.24 ± 0.18% and 2.03 ± 0.24% (w/w) of purpurin respectively. The study indicated that the most bioactive fraction of R. cordifolia (F4) and purpurin showed primarily monophenolase inhibition and to a lesser extent diphenolase inhibitory activity. In addition, results of enzyme kinetic analysis shown F4 and purpurin reversibly inhibited tyrosinase in a competitive manner. 1-Anilino-8-naphthalene sulfonate (ANS)-binding fluorescence measurement proved that conformation of tertiary structure of tyrosinase was not altered by Inhibitors. Although circular dichroism (CD) spectroscopy analysis showed that α-helical content of secondary structure decreased with increment of inhibitor's concentration. Molecular docking results implied that the possible inhibitory mechanisms may be attributed to purpurin interaction with copper ion coordinating three histidine residues (HIS61, HIS85, and HIS263) of tyrosinase. This finding could be of importance in prevention of the undesirable enzymatic browning reaction of food products, as well as hyper-pigmentation of human skin.
Lijun Song - One of the best experts on this subject based on the ideXlab platform.
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Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors
Journal of Medicinal Chemistry, 2018Co-Authors: Lijun Song, Hélène Munier-lehmann, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Begoña Gracia, Ainhoa Lucía Quintana, Paul Cos, José A. Aínsa, Savvas N. SavvidesAbstract:In recent years, thymidylate kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK ( MtTMPK) Inhibitors, and reported here the design of a novel series of non-nucleoside Inhibitors of MtTMPK. The Inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure-activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump Inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular Inhibitors increased significantly when determined for the efflux pump mmr knockout mutant, which partly explains the observed dissonance
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Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors
Journal of medicinal chemistry, 2018Co-Authors: Lijun Song, Hélène Munier-lehmann, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Begoña Gracia, Ainhoa Lucía Quintana, Paul Cos, José A. Aínsa, Savvas N. SavvidesAbstract:In recent years, thymidylate kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK (MtTMPK) Inhibitors, and reported here the design of a novel series of non-nucleoside Inhibitors of MtTMPK. The Inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure–activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump Inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular Inhibitors increased significantly when determined for the eff...
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Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors
2018Co-Authors: Lijun Song, Hélène Munier-lehmann, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Paul Cos, Begoña Gracia, Ainhoa Lucía Quintana, José A. Aínsa, Savvas N. SavvidesAbstract:In recent years, thymidylate kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK (MtTMPK) Inhibitors, and reported here the design of a novel series of non-nucleoside Inhibitors of MtTMPK. The Inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure–activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump Inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular Inhibitors increased significantly when determined for the efflux pump mmr knockout mutant, which partly explains the observed dissonance
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The design and synthesis of Inhibitors of Mycobacterium tuberculosis thymidylate kinase (MtTMPK)
2016Co-Authors: Lijun Song, Hélène Munier-lehmann, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Savvas N. Savvides, Serge Van CalenberghAbstract:Thymidylate kinase (TMPK) phosphorylates thymidine 5’-monophosphate (dTMP) to thymidine 5’-diphosphate (dTDP) and has been proposed as an attractive anti-tubercular target. By mimicking the structure of the substrate (dTMP), we have previously discovered different series of nucleoside analogues with Mycobacterium tuberculosis (Mt) TMPK inhibitory activities in the micromolar range. Based on recently reported potent piperidin-3-yl-thymine Inhibitors of Gram-positive bacterial TMPK, we report a series of isomeric N-benzyl-substituted piperidin-4-yl-thymine analogues, some of which demonstrate very promising MtTMPK inhibitory potency. This poster will discuss the synthesis, MtTMPK inhibitory activity, as well as structural data on how these new Inhibitors interact with the target enzyme.
Rajarshi Biswas - One of the best experts on this subject based on the ideXlab platform.
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tyrosinase inhibitory potential of purpurin in rubia cordifolia a bioactivity guided approach
Industrial Crops and Products, 2015Co-Authors: Rajarshi Biswas, Pulok K. Mukherjee, Manoj Kumar Dalai, Prasanta Mandal, Mrinmoy NagAbstract:Abstract The Rubia cordifolia Linn (Manjistha) is a wealthy resource of anthraquinones and its derivatives. In this study, the tyrosinase inhibitory potential of R. cordifolia (root extracts) was explored through bio-activity guided fractionation. Anti-tyrosinase assay guided fractionation led to obtained three different bioactive fractions, e.g ., F3, F4 and F5 from plant extract. Subsequent, Liquid chromatographic (RP-HPLC) analysis revealed the active fractions contained 0.89 ± 0.03%, 3.24 ± 0.18% and 2.03 ± 0.24% (w/w) of purpurin respectively. The study indicated that the most bioactive fraction of R. cordifolia (F4) and purpurin showed primarily monophenolase inhibition and to a lesser extent diphenolase inhibitory activity. In addition, results of enzyme kinetic analysis shown F4 and purpurin reversibly inhibited tyrosinase in a competitive manner. 1-Anilino-8-naphthalene sulfonate (ANS)-binding fluorescence measurement proved that conformation of tertiary structure of tyrosinase was not altered by Inhibitors. Although circular dichroism (CD) spectroscopy analysis showed that α-helical content of secondary structure decreased with increment of inhibitor's concentration. Molecular docking results implied that the possible inhibitory mechanisms may be attributed to purpurin interaction with copper ion coordinating three histidine residues (HIS61, HIS85, and HIS263) of tyrosinase. This finding could be of importance in prevention of the undesirable enzymatic browning reaction of food products, as well as hyper-pigmentation of human skin.
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Tyrosinase inhibitory potential of purpurin in Rubia cordifolia—A bioactivity guided approach
Industrial Crops and Products, 2015Co-Authors: Rajarshi Biswas, Pulok K. Mukherjee, Manoj Kumar Dalai, Prasanta Mandal, Mrinmoy NagAbstract:Abstract The Rubia cordifolia Linn (Manjistha) is a wealthy resource of anthraquinones and its derivatives. In this study, the tyrosinase inhibitory potential of R. cordifolia (root extracts) was explored through bio-activity guided fractionation. Anti-tyrosinase assay guided fractionation led to obtained three different bioactive fractions, e.g ., F3, F4 and F5 from plant extract. Subsequent, Liquid chromatographic (RP-HPLC) analysis revealed the active fractions contained 0.89 ± 0.03%, 3.24 ± 0.18% and 2.03 ± 0.24% (w/w) of purpurin respectively. The study indicated that the most bioactive fraction of R. cordifolia (F4) and purpurin showed primarily monophenolase inhibition and to a lesser extent diphenolase inhibitory activity. In addition, results of enzyme kinetic analysis shown F4 and purpurin reversibly inhibited tyrosinase in a competitive manner. 1-Anilino-8-naphthalene sulfonate (ANS)-binding fluorescence measurement proved that conformation of tertiary structure of tyrosinase was not altered by Inhibitors. Although circular dichroism (CD) spectroscopy analysis showed that α-helical content of secondary structure decreased with increment of inhibitor's concentration. Molecular docking results implied that the possible inhibitory mechanisms may be attributed to purpurin interaction with copper ion coordinating three histidine residues (HIS61, HIS85, and HIS263) of tyrosinase. This finding could be of importance in prevention of the undesirable enzymatic browning reaction of food products, as well as hyper-pigmentation of human skin.
Hélène Munier-lehmann - One of the best experts on this subject based on the ideXlab platform.
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Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors
Journal of Medicinal Chemistry, 2018Co-Authors: Lijun Song, Hélène Munier-lehmann, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Begoña Gracia, Ainhoa Lucía Quintana, Paul Cos, José A. Aínsa, Savvas N. SavvidesAbstract:In recent years, thymidylate kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK ( MtTMPK) Inhibitors, and reported here the design of a novel series of non-nucleoside Inhibitors of MtTMPK. The Inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure-activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump Inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular Inhibitors increased significantly when determined for the efflux pump mmr knockout mutant, which partly explains the observed dissonance
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Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors
Journal of medicinal chemistry, 2018Co-Authors: Lijun Song, Hélène Munier-lehmann, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Begoña Gracia, Ainhoa Lucía Quintana, Paul Cos, José A. Aínsa, Savvas N. SavvidesAbstract:In recent years, thymidylate kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK (MtTMPK) Inhibitors, and reported here the design of a novel series of non-nucleoside Inhibitors of MtTMPK. The Inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure–activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump Inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular Inhibitors increased significantly when determined for the eff...
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Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors
2018Co-Authors: Lijun Song, Hélène Munier-lehmann, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Paul Cos, Begoña Gracia, Ainhoa Lucía Quintana, José A. Aínsa, Savvas N. SavvidesAbstract:In recent years, thymidylate kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK (MtTMPK) Inhibitors, and reported here the design of a novel series of non-nucleoside Inhibitors of MtTMPK. The Inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure–activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump Inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular Inhibitors increased significantly when determined for the efflux pump mmr knockout mutant, which partly explains the observed dissonance
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The design and synthesis of Inhibitors of Mycobacterium tuberculosis thymidylate kinase (MtTMPK)
2016Co-Authors: Lijun Song, Hélène Munier-lehmann, Martijn Dp Risseeuw, Fabian Hulpia, Romain Merceron, Savvas N. Savvides, Serge Van CalenberghAbstract:Thymidylate kinase (TMPK) phosphorylates thymidine 5’-monophosphate (dTMP) to thymidine 5’-diphosphate (dTDP) and has been proposed as an attractive anti-tubercular target. By mimicking the structure of the substrate (dTMP), we have previously discovered different series of nucleoside analogues with Mycobacterium tuberculosis (Mt) TMPK inhibitory activities in the micromolar range. Based on recently reported potent piperidin-3-yl-thymine Inhibitors of Gram-positive bacterial TMPK, we report a series of isomeric N-benzyl-substituted piperidin-4-yl-thymine analogues, some of which demonstrate very promising MtTMPK inhibitory potency. This poster will discuss the synthesis, MtTMPK inhibitory activity, as well as structural data on how these new Inhibitors interact with the target enzyme.
