The Experts below are selected from a list of 13032 Experts worldwide ranked by ideXlab platform
Sungwoo Hong - One of the best experts on this subject based on the ideXlab platform.
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Discovery of Picomolar ABL Kinase Inhibitors Equipotent for Wild Type and T315I Mutant via Structure-Based de Novo Design
AMER CHEMICAL SOC, 2018Co-Authors: Hwangseo Park, Seunghee Hong, Jinhee Kim, Sungwoo HongAbstract:Although the constitutively activated break-point cluster region-Abelson (ABL) tyrosine kinase is known to cause chronic myelogenous leukemia (CML), the prevalence of drug-resistant ABL mutants has made it difficult to develop effective anti-CML drugs. With the aim to identify new lead compounds for anti-CML drugs, we carried out a structure-based de novo design using the scoring function improved by implementing an accurate solvation free energy term. This approach led to the identification of ABL Inhibitors equipotent for the wild type and the most drug-resistant T315I mutant of ABL at the picomolar level. Decomposition analysis of the binding free energy showed that a decrease in the desolvation cost for binding in the ATP-binding site could be as important as the strengthening of Enzyme-Inhibitor Interaction to enhance the potency of an ABL Inhibitor with structural modifications. A similar energetic feature was also observed in free energy perturbation (FEP) calculations. Consistent with the previous experimental and computational studies, the hydrogen bond Interactions with the backbone groups of Met318 proved to be the most significant binding forces to stabilize the Inhibitors in the ATP-binding sites of the wild type and T315I mutant. The results of molecular dynamics simulations indicated that the dyna222
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Discovery of Picomolar ABL Kinase Inhibitors Equipotent for Wild Type and T315I Mutant via Structure-Based de Novo Design
2016Co-Authors: Hwangseo Park, Seunghee Hong, Jinhee Kim, Sungwoo HongAbstract:Although the constitutively activated break-point cluster region–Abelson (ABL) tyrosine kinase is known to cause chronic myelogenous leukemia (CML), the prevalence of drug-resistant ABL mutants has made it difficult to develop effective anti-CML drugs. With the aim to identify new lead compounds for anti-CML drugs, we carried out a structure-based de novo design using the scoring function improved by implementing an accurate solvation free energy term. This approach led to the identification of ABL Inhibitors equipotent for the wild type and the most drug-resistant T315I mutant of ABL at the picomolar level. Decomposition analysis of the binding free energy showed that a decrease in the desolvation cost for binding in the ATP-binding site could be as important as the strengthening of Enzyme–Inhibitor Interaction to enhance the potency of an ABL Inhibitor with structural modifications. A similar energetic feature was also observed in free energy perturbation (FEP) calculations. Consistent with the previous experimental and computational studies, the hydrogen bond Interactions with the backbone groups of Met318 proved to be the most significant binding forces to stabilize the Inhibitors in the ATP-binding sites of the wild type and T315I mutant. The results of molecular dynamics simulations indicated that the dynamic stabilities of the hydrogen bonds between the Inhibitors and Met318 should also be considered in designing the potent common Inhibitors of the wild-type and T315I mutant of ABL
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discovery of picomolar abl kinase Inhibitors equipotent for wild type and t315i mutant via structure based de novo design
Journal of the American Chemical Society, 2013Co-Authors: Hwangseo Park, Seunghee Hong, Sungwoo HongAbstract:Although the constitutively activated break-point cluster region-Abelson (ABL) tyrosine kinase is known to cause chronic myelogenous leukemia (CML), the prevalence of drug-resistant ABL mutants has made it difficult to develop effective anti-CML drugs. With the aim to identify new lead compounds for anti-CML drugs, we carried out a structure-based de novo design using the scoring function improved by implementing an accurate solvation free energy term. This approach led to the identification of ABL Inhibitors equipotent for the wild type and the most drug-resistant T315I mutant of ABL at the picomolar level. Decomposition analysis of the binding free energy showed that a decrease in the desolvation cost for binding in the ATP-binding site could be as important as the strengthening of Enzyme-Inhibitor Interaction to enhance the potency of an ABL Inhibitor with structural modifications. A similar energetic feature was also observed in free energy perturbation (FEP) calculations. Consistent with the previous experimental and computational studies, the hydrogen bond Interactions with the backbone groups of Met318 proved to be the most significant binding forces to stabilize the Inhibitors in the ATP-binding sites of the wild type and T315I mutant. The results of molecular dynamics simulations indicated that the dynamic stabilities of the hydrogen bonds between the Inhibitors and Met318 should also be considered in designing the potent common Inhibitors of the wild-type and T315I mutant of ABL.
Stefano Alcaro - One of the best experts on this subject based on the ideXlab platform.
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investigations on the 2 thiazolylhydrazyne scaffold synthesis and molecular modeling of selective human monoamine oxidase Inhibitors
Bioorganic & Medicinal Chemistry, 2010Co-Authors: Franco Chimenti, Adriana Bolasco, Daniela Secci, Paola Chimenti, Arianna Granese, Simone Carradori, Matilde Yanez, Francisco Orallo, Francesco Ortuso, Stefano AlcaroAbstract:Abstract A new series of [4-(3-methoxyphenyl)-thiazol-2-yl]hydrazyne derivatives were synthesized in good yield (71–99%) and characterized by elemental analysis and 1H NMR studies. The compounds were assayed for their in vitro human monoamine oxidase (hMAO) Inhibitory activity and selectivity and most of them showed IC50 values in the nanomolar range, thus demonstrating our interest in this privileged scaffold. The most active and selective derivative (20), bearing a pyridine moiety on the C N, displayed IC50 = 3.81 ± 0.12 nM and selectivity ratio = 119 toward hMAO-B. Molecular modeling studies were carried out on recent and high resolution hMAO-A and hMAO-B crystallographic structures to better justify the Enzyme–Inhibitor Interaction toward hMAO isoforms and to explain the structure–activity relationship of this kind of Inhibitors.
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investigations on the 2 thiazolylhydrazyne scaffold synthesis and molecular modeling of selective human monoamine oxidase Inhibitors
Bioorganic & Medicinal Chemistry, 2010Co-Authors: Franco Chimenti, Adriana Bolasco, Daniela Secci, Paola Chimenti, Arianna Granese, Simone Carradori, Matilde Yanez, Francisco Orallo, Francesco Ortuso, Stefano AlcaroAbstract:A new series of [4-(3-methoxyphenyl)-thiazol-2-yl]hydrazyne derivatives were synthesized in good yield (71-99%) and characterized by elemental analysis and 1H NMR studies. The compounds were assayed for their in vitro human monoamine oxidase (hMAO) Inhibitory activity and selectivity and most of them showed IC50 values in the nanomolar range, thus demonstrating our interest in this privileged scaffold. The most active and selective derivative (20), bearing a pyridine moiety on the CN, displayed IC50 = 3.81 ± 0.12 nM and selectivity ratio = 119 toward hMAO-B. Molecular modeling studies were carried out on recent and high resolution hMAO-A and hMAO-B crystallographic structures to better justify the Enzyme-Inhibitor Interaction toward hMAO isoforms and to explain the structure-activity relationship of this kind of Inhibitors. © 2010 Elsevier Ltd.
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chalcones a valid scaffold for monoamine oxidases Inhibitors
Journal of Medicinal Chemistry, 2009Co-Authors: Franco Chimenti, Adriana Bolasco, Daniela Secci, Paola Chimenti, Matilde Yanez, Francisco Orallo, Francesco Ortuso, Rossella Fioravanti, Francesca Rossi, Stefano AlcaroAbstract:A large series of substituted chalcones have been synthesized and tested in vitro for their ability to inhibit human monoamine oxidases A and B (hMAO-A and hMAO-B). While all the compounds showed hMAO-B selective activity in the micro- and nanomolar ranges, the best results were obtained in the presence of chlorine and hydroxyl or methoxyl substituents. To better understand the Enzyme−Inhibitor Interaction and to explain the selectivity of the most active compounds toward hMAO-B, molecular modeling studies were carried out on new, high resolution, hMAO-B crystallographic structures. For the only compound that also showed activity against hMAO-A as well as low selectivity, the molecular modeling study was also performed on the hMAO-A crystallographic structure. The docking technique provided new insight on the inhibition mechanism and the rational drug design of more potent/selective hMAO Inhibitors based on the chalcone scaffold.
Franco Chimenti - One of the best experts on this subject based on the ideXlab platform.
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investigations on the 2 thiazolylhydrazyne scaffold synthesis and molecular modeling of selective human monoamine oxidase Inhibitors
Bioorganic & Medicinal Chemistry, 2010Co-Authors: Franco Chimenti, Adriana Bolasco, Daniela Secci, Paola Chimenti, Arianna Granese, Simone Carradori, Matilde Yanez, Francisco Orallo, Francesco Ortuso, Stefano AlcaroAbstract:Abstract A new series of [4-(3-methoxyphenyl)-thiazol-2-yl]hydrazyne derivatives were synthesized in good yield (71–99%) and characterized by elemental analysis and 1H NMR studies. The compounds were assayed for their in vitro human monoamine oxidase (hMAO) Inhibitory activity and selectivity and most of them showed IC50 values in the nanomolar range, thus demonstrating our interest in this privileged scaffold. The most active and selective derivative (20), bearing a pyridine moiety on the C N, displayed IC50 = 3.81 ± 0.12 nM and selectivity ratio = 119 toward hMAO-B. Molecular modeling studies were carried out on recent and high resolution hMAO-A and hMAO-B crystallographic structures to better justify the Enzyme–Inhibitor Interaction toward hMAO isoforms and to explain the structure–activity relationship of this kind of Inhibitors.
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investigations on the 2 thiazolylhydrazyne scaffold synthesis and molecular modeling of selective human monoamine oxidase Inhibitors
Bioorganic & Medicinal Chemistry, 2010Co-Authors: Franco Chimenti, Adriana Bolasco, Daniela Secci, Paola Chimenti, Arianna Granese, Simone Carradori, Matilde Yanez, Francisco Orallo, Francesco Ortuso, Stefano AlcaroAbstract:A new series of [4-(3-methoxyphenyl)-thiazol-2-yl]hydrazyne derivatives were synthesized in good yield (71-99%) and characterized by elemental analysis and 1H NMR studies. The compounds were assayed for their in vitro human monoamine oxidase (hMAO) Inhibitory activity and selectivity and most of them showed IC50 values in the nanomolar range, thus demonstrating our interest in this privileged scaffold. The most active and selective derivative (20), bearing a pyridine moiety on the CN, displayed IC50 = 3.81 ± 0.12 nM and selectivity ratio = 119 toward hMAO-B. Molecular modeling studies were carried out on recent and high resolution hMAO-A and hMAO-B crystallographic structures to better justify the Enzyme-Inhibitor Interaction toward hMAO isoforms and to explain the structure-activity relationship of this kind of Inhibitors. © 2010 Elsevier Ltd.
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chalcones a valid scaffold for monoamine oxidases Inhibitors
Journal of Medicinal Chemistry, 2009Co-Authors: Franco Chimenti, Adriana Bolasco, Daniela Secci, Paola Chimenti, Matilde Yanez, Francisco Orallo, Francesco Ortuso, Rossella Fioravanti, Francesca Rossi, Stefano AlcaroAbstract:A large series of substituted chalcones have been synthesized and tested in vitro for their ability to inhibit human monoamine oxidases A and B (hMAO-A and hMAO-B). While all the compounds showed hMAO-B selective activity in the micro- and nanomolar ranges, the best results were obtained in the presence of chlorine and hydroxyl or methoxyl substituents. To better understand the Enzyme−Inhibitor Interaction and to explain the selectivity of the most active compounds toward hMAO-B, molecular modeling studies were carried out on new, high resolution, hMAO-B crystallographic structures. For the only compound that also showed activity against hMAO-A as well as low selectivity, the molecular modeling study was also performed on the hMAO-A crystallographic structure. The docking technique provided new insight on the inhibition mechanism and the rational drug design of more potent/selective hMAO Inhibitors based on the chalcone scaffold.
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synthesis molecular modeling and selective Inhibitory activity against human monoamine oxidases of 3 carboxamido 7 substituted coumarins
Journal of Medicinal Chemistry, 2009Co-Authors: Franco Chimenti, Adriana Bolasco, Daniela Secci, Paola Chimenti, Arianna Granese, Simone Carradori, Matilde Yanez, Francisco Orallo, Bruna Bizzarri, Francesco OrtusoAbstract:A large series of 3-carboxamido-7-substituted coumarins have been synthesized and tested in vitro for their human monoamine oxidase A and B (hMAO-A and hMAO-B) Inhibitory activity. Taking into account all the relevant structural information on MAOs reported in the literature, we made some changes in the coumarin nucleus and examined with particular attention the effect on activity and selectivity of substituting at position 3 with N-aryl or N-alkyl carboxamide and at position 7 with a benzyloxy or a 4'-F-benzyloxy group. Some of the assayed compounds proved to be potent, selective Inhibitors of hMAO-B with IC(50) values in the micromolar range. To better understand the Enzyme-Inhibitor Interaction and to explain the selectivity of the most active compounds toward hMAOs, molecular modeling studies were carried out on new, high resolution, hMAO-A and hMAO-B crystallographic structures.
Hwangseo Park - One of the best experts on this subject based on the ideXlab platform.
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Discovery of Picomolar ABL Kinase Inhibitors Equipotent for Wild Type and T315I Mutant via Structure-Based de Novo Design
AMER CHEMICAL SOC, 2018Co-Authors: Hwangseo Park, Seunghee Hong, Jinhee Kim, Sungwoo HongAbstract:Although the constitutively activated break-point cluster region-Abelson (ABL) tyrosine kinase is known to cause chronic myelogenous leukemia (CML), the prevalence of drug-resistant ABL mutants has made it difficult to develop effective anti-CML drugs. With the aim to identify new lead compounds for anti-CML drugs, we carried out a structure-based de novo design using the scoring function improved by implementing an accurate solvation free energy term. This approach led to the identification of ABL Inhibitors equipotent for the wild type and the most drug-resistant T315I mutant of ABL at the picomolar level. Decomposition analysis of the binding free energy showed that a decrease in the desolvation cost for binding in the ATP-binding site could be as important as the strengthening of Enzyme-Inhibitor Interaction to enhance the potency of an ABL Inhibitor with structural modifications. A similar energetic feature was also observed in free energy perturbation (FEP) calculations. Consistent with the previous experimental and computational studies, the hydrogen bond Interactions with the backbone groups of Met318 proved to be the most significant binding forces to stabilize the Inhibitors in the ATP-binding sites of the wild type and T315I mutant. The results of molecular dynamics simulations indicated that the dyna222
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Discovery of Picomolar ABL Kinase Inhibitors Equipotent for Wild Type and T315I Mutant via Structure-Based de Novo Design
2016Co-Authors: Hwangseo Park, Seunghee Hong, Jinhee Kim, Sungwoo HongAbstract:Although the constitutively activated break-point cluster region–Abelson (ABL) tyrosine kinase is known to cause chronic myelogenous leukemia (CML), the prevalence of drug-resistant ABL mutants has made it difficult to develop effective anti-CML drugs. With the aim to identify new lead compounds for anti-CML drugs, we carried out a structure-based de novo design using the scoring function improved by implementing an accurate solvation free energy term. This approach led to the identification of ABL Inhibitors equipotent for the wild type and the most drug-resistant T315I mutant of ABL at the picomolar level. Decomposition analysis of the binding free energy showed that a decrease in the desolvation cost for binding in the ATP-binding site could be as important as the strengthening of Enzyme–Inhibitor Interaction to enhance the potency of an ABL Inhibitor with structural modifications. A similar energetic feature was also observed in free energy perturbation (FEP) calculations. Consistent with the previous experimental and computational studies, the hydrogen bond Interactions with the backbone groups of Met318 proved to be the most significant binding forces to stabilize the Inhibitors in the ATP-binding sites of the wild type and T315I mutant. The results of molecular dynamics simulations indicated that the dynamic stabilities of the hydrogen bonds between the Inhibitors and Met318 should also be considered in designing the potent common Inhibitors of the wild-type and T315I mutant of ABL
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discovery of picomolar abl kinase Inhibitors equipotent for wild type and t315i mutant via structure based de novo design
Journal of the American Chemical Society, 2013Co-Authors: Hwangseo Park, Seunghee Hong, Sungwoo HongAbstract:Although the constitutively activated break-point cluster region-Abelson (ABL) tyrosine kinase is known to cause chronic myelogenous leukemia (CML), the prevalence of drug-resistant ABL mutants has made it difficult to develop effective anti-CML drugs. With the aim to identify new lead compounds for anti-CML drugs, we carried out a structure-based de novo design using the scoring function improved by implementing an accurate solvation free energy term. This approach led to the identification of ABL Inhibitors equipotent for the wild type and the most drug-resistant T315I mutant of ABL at the picomolar level. Decomposition analysis of the binding free energy showed that a decrease in the desolvation cost for binding in the ATP-binding site could be as important as the strengthening of Enzyme-Inhibitor Interaction to enhance the potency of an ABL Inhibitor with structural modifications. A similar energetic feature was also observed in free energy perturbation (FEP) calculations. Consistent with the previous experimental and computational studies, the hydrogen bond Interactions with the backbone groups of Met318 proved to be the most significant binding forces to stabilize the Inhibitors in the ATP-binding sites of the wild type and T315I mutant. The results of molecular dynamics simulations indicated that the dynamic stabilities of the hydrogen bonds between the Inhibitors and Met318 should also be considered in designing the potent common Inhibitors of the wild-type and T315I mutant of ABL.
Francesco Ortuso - One of the best experts on this subject based on the ideXlab platform.
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investigations on the 2 thiazolylhydrazyne scaffold synthesis and molecular modeling of selective human monoamine oxidase Inhibitors
Bioorganic & Medicinal Chemistry, 2010Co-Authors: Franco Chimenti, Adriana Bolasco, Daniela Secci, Paola Chimenti, Arianna Granese, Simone Carradori, Matilde Yanez, Francisco Orallo, Francesco Ortuso, Stefano AlcaroAbstract:Abstract A new series of [4-(3-methoxyphenyl)-thiazol-2-yl]hydrazyne derivatives were synthesized in good yield (71–99%) and characterized by elemental analysis and 1H NMR studies. The compounds were assayed for their in vitro human monoamine oxidase (hMAO) Inhibitory activity and selectivity and most of them showed IC50 values in the nanomolar range, thus demonstrating our interest in this privileged scaffold. The most active and selective derivative (20), bearing a pyridine moiety on the C N, displayed IC50 = 3.81 ± 0.12 nM and selectivity ratio = 119 toward hMAO-B. Molecular modeling studies were carried out on recent and high resolution hMAO-A and hMAO-B crystallographic structures to better justify the Enzyme–Inhibitor Interaction toward hMAO isoforms and to explain the structure–activity relationship of this kind of Inhibitors.
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investigations on the 2 thiazolylhydrazyne scaffold synthesis and molecular modeling of selective human monoamine oxidase Inhibitors
Bioorganic & Medicinal Chemistry, 2010Co-Authors: Franco Chimenti, Adriana Bolasco, Daniela Secci, Paola Chimenti, Arianna Granese, Simone Carradori, Matilde Yanez, Francisco Orallo, Francesco Ortuso, Stefano AlcaroAbstract:A new series of [4-(3-methoxyphenyl)-thiazol-2-yl]hydrazyne derivatives were synthesized in good yield (71-99%) and characterized by elemental analysis and 1H NMR studies. The compounds were assayed for their in vitro human monoamine oxidase (hMAO) Inhibitory activity and selectivity and most of them showed IC50 values in the nanomolar range, thus demonstrating our interest in this privileged scaffold. The most active and selective derivative (20), bearing a pyridine moiety on the CN, displayed IC50 = 3.81 ± 0.12 nM and selectivity ratio = 119 toward hMAO-B. Molecular modeling studies were carried out on recent and high resolution hMAO-A and hMAO-B crystallographic structures to better justify the Enzyme-Inhibitor Interaction toward hMAO isoforms and to explain the structure-activity relationship of this kind of Inhibitors. © 2010 Elsevier Ltd.
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chalcones a valid scaffold for monoamine oxidases Inhibitors
Journal of Medicinal Chemistry, 2009Co-Authors: Franco Chimenti, Adriana Bolasco, Daniela Secci, Paola Chimenti, Matilde Yanez, Francisco Orallo, Francesco Ortuso, Rossella Fioravanti, Francesca Rossi, Stefano AlcaroAbstract:A large series of substituted chalcones have been synthesized and tested in vitro for their ability to inhibit human monoamine oxidases A and B (hMAO-A and hMAO-B). While all the compounds showed hMAO-B selective activity in the micro- and nanomolar ranges, the best results were obtained in the presence of chlorine and hydroxyl or methoxyl substituents. To better understand the Enzyme−Inhibitor Interaction and to explain the selectivity of the most active compounds toward hMAO-B, molecular modeling studies were carried out on new, high resolution, hMAO-B crystallographic structures. For the only compound that also showed activity against hMAO-A as well as low selectivity, the molecular modeling study was also performed on the hMAO-A crystallographic structure. The docking technique provided new insight on the inhibition mechanism and the rational drug design of more potent/selective hMAO Inhibitors based on the chalcone scaffold.
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synthesis molecular modeling and selective Inhibitory activity against human monoamine oxidases of 3 carboxamido 7 substituted coumarins
Journal of Medicinal Chemistry, 2009Co-Authors: Franco Chimenti, Adriana Bolasco, Daniela Secci, Paola Chimenti, Arianna Granese, Simone Carradori, Matilde Yanez, Francisco Orallo, Bruna Bizzarri, Francesco OrtusoAbstract:A large series of 3-carboxamido-7-substituted coumarins have been synthesized and tested in vitro for their human monoamine oxidase A and B (hMAO-A and hMAO-B) Inhibitory activity. Taking into account all the relevant structural information on MAOs reported in the literature, we made some changes in the coumarin nucleus and examined with particular attention the effect on activity and selectivity of substituting at position 3 with N-aryl or N-alkyl carboxamide and at position 7 with a benzyloxy or a 4'-F-benzyloxy group. Some of the assayed compounds proved to be potent, selective Inhibitors of hMAO-B with IC(50) values in the micromolar range. To better understand the Enzyme-Inhibitor Interaction and to explain the selectivity of the most active compounds toward hMAOs, molecular modeling studies were carried out on new, high resolution, hMAO-A and hMAO-B crystallographic structures.