Tímea Polgár - Academia.edu (original) (raw)
Papers by Tímea Polgár
International Journal of Food Sciences and Nutrition, 2019
Total-scale quantitative research literature analysis on the food toxicology scientific field has... more Total-scale quantitative research literature analysis on the food toxicology scientific field has yet to be conducted. In this work, we identified and analysed food toxicology publications in the existing scientific literature. A literature search was performed with the online Web of Science database. Full records and cited references of the 73,099 identified manuscripts were imported into VOSviewer software for analysis. This research field has been growing steadily since the 1990s. Article to review ratio was 7.4:1. The publications were mainly related to toxicology, environmental sciences, food science and technology, pharmacology/pharmacy and biochemistry/ molecular biology. The United States and China are major contributors to food toxicology research, followed by other European and Asian countries. The prolific authors have formed three major clusters within a citation network. Toxic or hazardous chemicals related to food with high citations included aflatoxin, dioxin, fumonisin, malondialdehyde, mycotoxin, ochratoxin, phthalate, and polychlorinated biphenyl.
Journal of Biological Chemistry, 2010
Using structure-based virtual screening, we previously identified a novel stilbenoid inhibitor of... more Using structure-based virtual screening, we previously identified a novel stilbenoid inhibitor of Jak2 tyrosine kinase named G6. Here, we hypothesized that G6 suppresses Jak2-V617F-mediated human pathological cell growth in vitro and in vivo. We found that G6 inhibited proliferation of the Jak2-V617F expressing human erythroleukemia (HEL) cell line by promoting marked cell cycle arrest and inducing apoptosis. The G6-dependent increase in apoptosis levels was concomitant with increased caspase 3/7 activity and cleavage of PARP. G6 also selectively inhibited phosphorylation of STAT5, a downstream signaling target of Jak2. Using a mouse model of Jak2-V617F-mediated hyperplasia, we found that G6 significantly decreased the percentage of blast cells in the peripheral blood, reduced splenomegaly, and corrected a pathologically low myeloid to erythroid ratio in the bone marrow by eliminating HEL cell engraftment in this tissue. In addition, drug efficacy correlated with the presence of G6 in the plasma, marrow, and spleen. Collectively, these data demonstrate that the stilbenoid compound, G6, suppresses Jak2-V617F-mediated aberrant cell growth. As such, G6 may be a potential therapeutic lead candidate against Jak2-mediated, human disease.
Journal of Biological Chemistry, 2004
Control of mitogen-activated protein kinase (MAPK) cascades is central to regulation of many cell... more Control of mitogen-activated protein kinase (MAPK) cascades is central to regulation of many cellular responses. We describe here human tribbles homologues (Htrbs) that control MAPK activity. MAPK kinases interact with Trbs and regulate their steady state levels. Further, Trbs selectively regulate the activation of extracellular signal-regulated kinases, c-Jun NH 2-terminal kinases, and p38 MAPK with different relative levels of activity for the three classes of MAPK observed depending on the level of Trb expression. These results suggest that Trbs control both the extent and the specificity of MAPK kinase activation of MAPK.
QSAR & Combinatorial Science, 2009
The predictive performance of five different pK a prediction tools (ACDpKa, Epik, Marvin pKa, Pal... more The predictive performance of five different pK a prediction tools (ACDpKa, Epik, Marvin pKa, Pallas pKa, and VCCpKa) was investigated on the 248-membered Gold Standard dataset. We found VCC as the most predictive, high throughput pK a predictor. However since VCC calculates pK a for the most acidic or basic group only we concluded that ACD and Marvin are in fact the method of choice for medicinal chemistry applications. Analyzing the common outliers we identified guanidines, enolic hydroxyl groups and weak acidic NHs as most problematic moieties from prediction point of view. Our results obtained on the high quality, homogenous Gold Standard dataset could be useful for end-users selecting a suitable solution for pK a prediction.
In this paper, we present our annotation tool that facilitates research and annotation work by qu... more In this paper, we present our annotation tool that facilitates research and annotation work by quick, yet efficient literature processing. Our tool helps users create a unique and refined collection of linked information, which can lead to more effective and faster decisions in research. The tool is currently optimized for biomedical domain, but it can adapted to other academic fields with minimal efforts
XV. Magyar Gyógynövény Konferencia, 2018
Molecules, 2019
The current study aimed to provide a comprehensive bibliometric overview of the literature on cur... more The current study aimed to provide a comprehensive bibliometric overview of the literature on curcumin, complementing the previous reviews and meta-analyses on its potential health benefits. Bibliometric data for the current analysis were extracted from the Web of Science Core Collection database, using the search string TOPIC=(“curcumin*”), and analyzed by the VOSviewer software. The search yielded 18,036 manuscripts. The ratio of original articles to reviews was 10.4:1. More than half of the papers have been published since 2014. The major contributing countries were the United States, China, India, Japan, and South Korea. These publications were mainly published in journals representing the following scientific disciplines: biochemistry, chemistry, oncology, and pharmacology. There was a significant positive correlation between the total publication count and averaged citations per manuscript for affiliations, but not for countries/regions and journals. Chemicals that were freque...
Acta pharmaceutica Hungarica, 2007
Identification of a viable lead is a critical step in drug discovery. The qualities of the lead s... more Identification of a viable lead is a critical step in drug discovery. The qualities of the lead set the stage for subsequent efforts to ameliorate therapeutic efficacy through potency, selectivity, pharmacokinetics, toxicity and side effects. In a retrospective view of drug research the lead identification has been realised mainly by in vivo methodologies. However, limitations of in vivo models were found to be critical factors when analysing attrition rates that prompted research groups to introduce in vitro tests and rational approaches at the frontline of discovery programs. Virtual screening (VS) methods merge in vitro high-throughput (HTS) and rational approaches. The VS methods can be classified as ligand and structure based techniques. Structure based approaches depart from the structural information of the target to identify potential interactions between the ligands and the protein. The advantages and disadvantages and the applicability of the structure based virtual screen...
Current Pharmaceutical Design, 2014
Combinatorial Chemistry & High Throughput Screening, 2011
In the last decade mass screening strategies became the main source of leads in drug discovery se... more In the last decade mass screening strategies became the main source of leads in drug discovery settings. Although high throughput (HTS) and virtual screening (VS) realize the same concept the different nature of these lead discovery strategies (experimental vs theoretical) results that they are typically applied separately. The majority of drug leads are still identified by hit-to-lead optimization of screening hits. Structural information on the target as well as on bound ligands, however, make structure-based and ligand-based virtual screening available for the identification of alternative chemical starting points. Although, the two techniques have rarely been used together on the same target, here we review the existing prominent studies on their true integration. Various approaches have been shown to apply the combination of HTS and VS and to better use them in lead generation. Although several attempts on their integration have only been considered at a conceptual level, there are numerous applications underlining its relevance that early-stage pharmaceutical drug research could benefit from a combined approach.
Journal of Chemical Information and Modeling, 2014
3D shape-or volume-based virtual screening is a broadly used approach in drug discovery. In recen... more 3D shape-or volume-based virtual screening is a broadly used approach in drug discovery. In recent years a large number of publications have appeared in which these tools were compared not only to competitive methods but to docking studies as well. Studies often showed that the effectiveness of docking could be highly variable due to a large number of possible confounding factors, while ligand-based, shape-based approaches were more consistent. Here, we describe a novel, fully flexible shape-based virtual screening algorithm that does not require previous 3D conformation or conformer generation. Due to its solid consistency it can easily be used on desktop computers by non-expert scientists. The algorithm is demonstrated in a study for the investigation of β-secretase inhibitors and benchmarked on the Directory of Useful Decoys data set.
Annals of The New York Academy of Sciences, 2005
Abstract: Macrophages activated by lipopolysaccharide and/or phorbol esters exhibited high sensit... more Abstract: Macrophages activated by lipopolysaccharide and/or phorbol esters exhibited high sensitivity to Avemar, a fermented wheat germ extract. Avemar synergized with lipopolysaccharide and PMA in the induction of the transcription of cytokine genes and release of inflammatory cytokines. At higher concentrations the preparation had a significant negative effect on the proliferation and survival of activated myeloid cell types. Avemar treatment induced the synthesis of ICAM-1 and synergized with the ICAM-inducing effect of TNF, but had no effect on VCAM-1 expression on microvascular endothelial cells. The effect of Avemar on signaling pathways, which are involved in cell activation was studied on HeLa cells as a model system. Avemar treatment increased the activity of stress kinases in a concentration-dependent way, resulting in the activation of AP-1 transcription factor. NF-kappa B-sensitive reporters were also activated by Avemar; in contrast, no effect of the preparation was observed on PKA-sensitive signaling pathways.
Biochemical Society Transactions, 2005
Multiple cellular proteins have been identified as participating in Toll/interleukin-1 receptor-m... more Multiple cellular proteins have been identified as participating in Toll/interleukin-1 receptor-mediated inflammatory gene expression. The continuing isolation of novel components, based on sequence similarities, protein-protein interactions and protein purification, suggests that many elements of this signalling network remain to be identified. We report here the development of a high-throughput functional screening platform and its application for the identification of components of inflammatory signalling networks. Our results enable us to estimate that 100-150 gene products are involved in controlling the transcription of the human interleukin 8 gene. The approach, which is simple and robust, constitutes a general method for mapping signal transduction systems and for rapid isolation of a large number of signalling components based on the control of pathways leading to regulation of gene expression.
Cellular Signalling, 2006
Sustained inflammatory responses are central to the development and progression of chronic diseas... more Sustained inflammatory responses are central to the development and progression of chronic diseases, including atherosclerosis and rheumatoid arthritis. A large number of stimuli initiate inflammation by acting on Toll -Interleukin-1 related (TIR) domain containing receptors, producing multiple second messengers and thence large scale transcriptional changes. The mechanism by which this activation occurs is complex, and the continuing isolation of novel pathway components, mostly based on sequence similarities and protein -protein interaction studies, suggests that many elements of the TIR-initiated signalling network remain to be identified. Here we use a new technique, allowing identification of components based on function. We report the performance of the screen, our identification of human tribbles as a novel protein family regulating inflammatory signalling networks, and the detection of ten other components with poorly characterized roles in inflammatory signalling pathways. In total, we have identified 28 signalling molecules of diverse molecular mechanism by screening 11% of a cDNA library for the ability to modulation expression of human IL-8, and other molecules remain to be followed up. The results suggest that the number of human genes involved in IL-8 induction pathways exceed 100. The isolation of signalling components by the approach we describe allows detection of new classes of signalling components independent of existing techniques for doing so; it is simple and robust, and constitutes a general method for mapping signal transduction systems controlling gene expression. D
Journal of Medicinal Chemistry, 2005
Glycogen synthase kinase-3 (GSK-3 ) is a serine/threonine kinase that has recently emerged as a k... more Glycogen synthase kinase-3 (GSK-3 ) is a serine/threonine kinase that has recently emerged as a key target for neurodegenerative diseases and diabetes. As an initial step of our lead discovery program, we developed a virtual screen to discriminate known GSK-3 inhibitors and inactive compounds using FlexX, FlexX-Pharm, and FlexE. The maximal enrichment factor (EF ) 28) suggests that our protocol identifies potential GSK-3 inhibitors effectively from large compound collections. The effectiveness of our screening protocol was further investigated by comparative experimental and virtual high-throughput screens (HTSs) performed for the same subset of our corporate library. Enrichment factors, the significantly higher hit rate of virtual screening (12.9%) than that of the HTS (0.55%), and also the comparison of active clusters suggest that our virtual screening protocol is an effective tool in GSK-3 -based library focusing. Head-to-head comparison of true/false positives and negatives revealed the two approaches to be complementary rather than competitive. . Inhibition % vs FlexX score. Filled black circles show HTS hits that were not validated. The 1% level of the ranked database is at FlexX score ) -26.4. From the 90 validated HTS hits, only 41 could be docked using FlexX-Pharm; 49 did not fulfill the pharmacophore constraints; therefore, these cannot be plotted here.
Journal of Molecular Structure-theochem, 2003
ABSTRACT The biological role of many medical herbs used in traditional Chinese medicine has alrea... more ABSTRACT The biological role of many medical herbs used in traditional Chinese medicine has already been studied. The antimutagenic activity of BZ's ((E)-4-phenylbut-3-en-2-ones) derivatives isolated from Scutellaria barbata was quantitatively analyzed in term of physicochemical parameters. Popelier et al. carried out a quantum topological molecular similarity study on a set of 15 phenylbutenone derivatives. The equilibrium geometries of the molecules in question were determined at the HF/6-31G(d) level of theory. According to their results, all the trial conformations collapsed to the planar configuration with Cs symmetry. This short paper presents that at the second order Møller–Plesset level of theory at least two chiral conformers exist in each case. Of the set of 15 phenylbutenone derivatives, two representative examples were chosen to demonstrate the results of the conformational analysis.
Journal of Medicinal Chemistry, 2005
A comparative virtual screen for beta-secretase (BACE1) inhibitors using different docking method... more A comparative virtual screen for beta-secretase (BACE1) inhibitors using different docking methods (FlexX and FlexX-Pharm), scoring functions (Dock, Gold, Chem, PMF, FlexX), protonation states (default and calculated), and protein conformations (apo and ligand bound) has been performed. Apo and ligand bound conformations of BACE1 were both found to be suitable for virtual screening. Assigning calculated protonation states to catalytic Asp32 and Asp228 residues resulted in significant improvement of enrichment factors as calculated at 1% of the ranked database. Using 1FKN we obtained no enrichment by FlexX/D-Score that was improved to 36 when considering calculated protonation states. We also show that combining calculated protonation states with pharmacophore constraints using FlexX-Pharm/D-Score improved enrichment further to 41. Enrichments reported in this study suggest our screening protocol will be effective in the virtual screening of large compound libraries for BACE1 inhibitors.
Cheminform, 2006
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.
International Journal of Food Sciences and Nutrition, 2019
Total-scale quantitative research literature analysis on the food toxicology scientific field has... more Total-scale quantitative research literature analysis on the food toxicology scientific field has yet to be conducted. In this work, we identified and analysed food toxicology publications in the existing scientific literature. A literature search was performed with the online Web of Science database. Full records and cited references of the 73,099 identified manuscripts were imported into VOSviewer software for analysis. This research field has been growing steadily since the 1990s. Article to review ratio was 7.4:1. The publications were mainly related to toxicology, environmental sciences, food science and technology, pharmacology/pharmacy and biochemistry/ molecular biology. The United States and China are major contributors to food toxicology research, followed by other European and Asian countries. The prolific authors have formed three major clusters within a citation network. Toxic or hazardous chemicals related to food with high citations included aflatoxin, dioxin, fumonisin, malondialdehyde, mycotoxin, ochratoxin, phthalate, and polychlorinated biphenyl.
Journal of Biological Chemistry, 2010
Using structure-based virtual screening, we previously identified a novel stilbenoid inhibitor of... more Using structure-based virtual screening, we previously identified a novel stilbenoid inhibitor of Jak2 tyrosine kinase named G6. Here, we hypothesized that G6 suppresses Jak2-V617F-mediated human pathological cell growth in vitro and in vivo. We found that G6 inhibited proliferation of the Jak2-V617F expressing human erythroleukemia (HEL) cell line by promoting marked cell cycle arrest and inducing apoptosis. The G6-dependent increase in apoptosis levels was concomitant with increased caspase 3/7 activity and cleavage of PARP. G6 also selectively inhibited phosphorylation of STAT5, a downstream signaling target of Jak2. Using a mouse model of Jak2-V617F-mediated hyperplasia, we found that G6 significantly decreased the percentage of blast cells in the peripheral blood, reduced splenomegaly, and corrected a pathologically low myeloid to erythroid ratio in the bone marrow by eliminating HEL cell engraftment in this tissue. In addition, drug efficacy correlated with the presence of G6 in the plasma, marrow, and spleen. Collectively, these data demonstrate that the stilbenoid compound, G6, suppresses Jak2-V617F-mediated aberrant cell growth. As such, G6 may be a potential therapeutic lead candidate against Jak2-mediated, human disease.
Journal of Biological Chemistry, 2004
Control of mitogen-activated protein kinase (MAPK) cascades is central to regulation of many cell... more Control of mitogen-activated protein kinase (MAPK) cascades is central to regulation of many cellular responses. We describe here human tribbles homologues (Htrbs) that control MAPK activity. MAPK kinases interact with Trbs and regulate their steady state levels. Further, Trbs selectively regulate the activation of extracellular signal-regulated kinases, c-Jun NH 2-terminal kinases, and p38 MAPK with different relative levels of activity for the three classes of MAPK observed depending on the level of Trb expression. These results suggest that Trbs control both the extent and the specificity of MAPK kinase activation of MAPK.
QSAR & Combinatorial Science, 2009
The predictive performance of five different pK a prediction tools (ACDpKa, Epik, Marvin pKa, Pal... more The predictive performance of five different pK a prediction tools (ACDpKa, Epik, Marvin pKa, Pallas pKa, and VCCpKa) was investigated on the 248-membered Gold Standard dataset. We found VCC as the most predictive, high throughput pK a predictor. However since VCC calculates pK a for the most acidic or basic group only we concluded that ACD and Marvin are in fact the method of choice for medicinal chemistry applications. Analyzing the common outliers we identified guanidines, enolic hydroxyl groups and weak acidic NHs as most problematic moieties from prediction point of view. Our results obtained on the high quality, homogenous Gold Standard dataset could be useful for end-users selecting a suitable solution for pK a prediction.
In this paper, we present our annotation tool that facilitates research and annotation work by qu... more In this paper, we present our annotation tool that facilitates research and annotation work by quick, yet efficient literature processing. Our tool helps users create a unique and refined collection of linked information, which can lead to more effective and faster decisions in research. The tool is currently optimized for biomedical domain, but it can adapted to other academic fields with minimal efforts
XV. Magyar Gyógynövény Konferencia, 2018
Molecules, 2019
The current study aimed to provide a comprehensive bibliometric overview of the literature on cur... more The current study aimed to provide a comprehensive bibliometric overview of the literature on curcumin, complementing the previous reviews and meta-analyses on its potential health benefits. Bibliometric data for the current analysis were extracted from the Web of Science Core Collection database, using the search string TOPIC=(“curcumin*”), and analyzed by the VOSviewer software. The search yielded 18,036 manuscripts. The ratio of original articles to reviews was 10.4:1. More than half of the papers have been published since 2014. The major contributing countries were the United States, China, India, Japan, and South Korea. These publications were mainly published in journals representing the following scientific disciplines: biochemistry, chemistry, oncology, and pharmacology. There was a significant positive correlation between the total publication count and averaged citations per manuscript for affiliations, but not for countries/regions and journals. Chemicals that were freque...
Acta pharmaceutica Hungarica, 2007
Identification of a viable lead is a critical step in drug discovery. The qualities of the lead s... more Identification of a viable lead is a critical step in drug discovery. The qualities of the lead set the stage for subsequent efforts to ameliorate therapeutic efficacy through potency, selectivity, pharmacokinetics, toxicity and side effects. In a retrospective view of drug research the lead identification has been realised mainly by in vivo methodologies. However, limitations of in vivo models were found to be critical factors when analysing attrition rates that prompted research groups to introduce in vitro tests and rational approaches at the frontline of discovery programs. Virtual screening (VS) methods merge in vitro high-throughput (HTS) and rational approaches. The VS methods can be classified as ligand and structure based techniques. Structure based approaches depart from the structural information of the target to identify potential interactions between the ligands and the protein. The advantages and disadvantages and the applicability of the structure based virtual screen...
Current Pharmaceutical Design, 2014
Combinatorial Chemistry & High Throughput Screening, 2011
In the last decade mass screening strategies became the main source of leads in drug discovery se... more In the last decade mass screening strategies became the main source of leads in drug discovery settings. Although high throughput (HTS) and virtual screening (VS) realize the same concept the different nature of these lead discovery strategies (experimental vs theoretical) results that they are typically applied separately. The majority of drug leads are still identified by hit-to-lead optimization of screening hits. Structural information on the target as well as on bound ligands, however, make structure-based and ligand-based virtual screening available for the identification of alternative chemical starting points. Although, the two techniques have rarely been used together on the same target, here we review the existing prominent studies on their true integration. Various approaches have been shown to apply the combination of HTS and VS and to better use them in lead generation. Although several attempts on their integration have only been considered at a conceptual level, there are numerous applications underlining its relevance that early-stage pharmaceutical drug research could benefit from a combined approach.
Journal of Chemical Information and Modeling, 2014
3D shape-or volume-based virtual screening is a broadly used approach in drug discovery. In recen... more 3D shape-or volume-based virtual screening is a broadly used approach in drug discovery. In recent years a large number of publications have appeared in which these tools were compared not only to competitive methods but to docking studies as well. Studies often showed that the effectiveness of docking could be highly variable due to a large number of possible confounding factors, while ligand-based, shape-based approaches were more consistent. Here, we describe a novel, fully flexible shape-based virtual screening algorithm that does not require previous 3D conformation or conformer generation. Due to its solid consistency it can easily be used on desktop computers by non-expert scientists. The algorithm is demonstrated in a study for the investigation of β-secretase inhibitors and benchmarked on the Directory of Useful Decoys data set.
Annals of The New York Academy of Sciences, 2005
Abstract: Macrophages activated by lipopolysaccharide and/or phorbol esters exhibited high sensit... more Abstract: Macrophages activated by lipopolysaccharide and/or phorbol esters exhibited high sensitivity to Avemar, a fermented wheat germ extract. Avemar synergized with lipopolysaccharide and PMA in the induction of the transcription of cytokine genes and release of inflammatory cytokines. At higher concentrations the preparation had a significant negative effect on the proliferation and survival of activated myeloid cell types. Avemar treatment induced the synthesis of ICAM-1 and synergized with the ICAM-inducing effect of TNF, but had no effect on VCAM-1 expression on microvascular endothelial cells. The effect of Avemar on signaling pathways, which are involved in cell activation was studied on HeLa cells as a model system. Avemar treatment increased the activity of stress kinases in a concentration-dependent way, resulting in the activation of AP-1 transcription factor. NF-kappa B-sensitive reporters were also activated by Avemar; in contrast, no effect of the preparation was observed on PKA-sensitive signaling pathways.
Biochemical Society Transactions, 2005
Multiple cellular proteins have been identified as participating in Toll/interleukin-1 receptor-m... more Multiple cellular proteins have been identified as participating in Toll/interleukin-1 receptor-mediated inflammatory gene expression. The continuing isolation of novel components, based on sequence similarities, protein-protein interactions and protein purification, suggests that many elements of this signalling network remain to be identified. We report here the development of a high-throughput functional screening platform and its application for the identification of components of inflammatory signalling networks. Our results enable us to estimate that 100-150 gene products are involved in controlling the transcription of the human interleukin 8 gene. The approach, which is simple and robust, constitutes a general method for mapping signal transduction systems and for rapid isolation of a large number of signalling components based on the control of pathways leading to regulation of gene expression.
Cellular Signalling, 2006
Sustained inflammatory responses are central to the development and progression of chronic diseas... more Sustained inflammatory responses are central to the development and progression of chronic diseases, including atherosclerosis and rheumatoid arthritis. A large number of stimuli initiate inflammation by acting on Toll -Interleukin-1 related (TIR) domain containing receptors, producing multiple second messengers and thence large scale transcriptional changes. The mechanism by which this activation occurs is complex, and the continuing isolation of novel pathway components, mostly based on sequence similarities and protein -protein interaction studies, suggests that many elements of the TIR-initiated signalling network remain to be identified. Here we use a new technique, allowing identification of components based on function. We report the performance of the screen, our identification of human tribbles as a novel protein family regulating inflammatory signalling networks, and the detection of ten other components with poorly characterized roles in inflammatory signalling pathways. In total, we have identified 28 signalling molecules of diverse molecular mechanism by screening 11% of a cDNA library for the ability to modulation expression of human IL-8, and other molecules remain to be followed up. The results suggest that the number of human genes involved in IL-8 induction pathways exceed 100. The isolation of signalling components by the approach we describe allows detection of new classes of signalling components independent of existing techniques for doing so; it is simple and robust, and constitutes a general method for mapping signal transduction systems controlling gene expression. D
Journal of Medicinal Chemistry, 2005
Glycogen synthase kinase-3 (GSK-3 ) is a serine/threonine kinase that has recently emerged as a k... more Glycogen synthase kinase-3 (GSK-3 ) is a serine/threonine kinase that has recently emerged as a key target for neurodegenerative diseases and diabetes. As an initial step of our lead discovery program, we developed a virtual screen to discriminate known GSK-3 inhibitors and inactive compounds using FlexX, FlexX-Pharm, and FlexE. The maximal enrichment factor (EF ) 28) suggests that our protocol identifies potential GSK-3 inhibitors effectively from large compound collections. The effectiveness of our screening protocol was further investigated by comparative experimental and virtual high-throughput screens (HTSs) performed for the same subset of our corporate library. Enrichment factors, the significantly higher hit rate of virtual screening (12.9%) than that of the HTS (0.55%), and also the comparison of active clusters suggest that our virtual screening protocol is an effective tool in GSK-3 -based library focusing. Head-to-head comparison of true/false positives and negatives revealed the two approaches to be complementary rather than competitive. . Inhibition % vs FlexX score. Filled black circles show HTS hits that were not validated. The 1% level of the ranked database is at FlexX score ) -26.4. From the 90 validated HTS hits, only 41 could be docked using FlexX-Pharm; 49 did not fulfill the pharmacophore constraints; therefore, these cannot be plotted here.
Journal of Molecular Structure-theochem, 2003
ABSTRACT The biological role of many medical herbs used in traditional Chinese medicine has alrea... more ABSTRACT The biological role of many medical herbs used in traditional Chinese medicine has already been studied. The antimutagenic activity of BZ's ((E)-4-phenylbut-3-en-2-ones) derivatives isolated from Scutellaria barbata was quantitatively analyzed in term of physicochemical parameters. Popelier et al. carried out a quantum topological molecular similarity study on a set of 15 phenylbutenone derivatives. The equilibrium geometries of the molecules in question were determined at the HF/6-31G(d) level of theory. According to their results, all the trial conformations collapsed to the planar configuration with Cs symmetry. This short paper presents that at the second order Møller–Plesset level of theory at least two chiral conformers exist in each case. Of the set of 15 phenylbutenone derivatives, two representative examples were chosen to demonstrate the results of the conformational analysis.
Journal of Medicinal Chemistry, 2005
A comparative virtual screen for beta-secretase (BACE1) inhibitors using different docking method... more A comparative virtual screen for beta-secretase (BACE1) inhibitors using different docking methods (FlexX and FlexX-Pharm), scoring functions (Dock, Gold, Chem, PMF, FlexX), protonation states (default and calculated), and protein conformations (apo and ligand bound) has been performed. Apo and ligand bound conformations of BACE1 were both found to be suitable for virtual screening. Assigning calculated protonation states to catalytic Asp32 and Asp228 residues resulted in significant improvement of enrichment factors as calculated at 1% of the ranked database. Using 1FKN we obtained no enrichment by FlexX/D-Score that was improved to 36 when considering calculated protonation states. We also show that combining calculated protonation states with pharmacophore constraints using FlexX-Pharm/D-Score improved enrichment further to 41. Enrichments reported in this study suggest our screening protocol will be effective in the virtual screening of large compound libraries for BACE1 inhibitors.
Cheminform, 2006
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.