The Experts below are selected from a list of 59502 Experts worldwide ranked by ideXlab platform
Dongdong Sun - One of the best experts on this subject based on the ideXlab platform.
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Rational creation and systematic analysis of cervical cancer kinase–inhibitor Binding Profile
Journal of Computer-Aided Molecular Design, 2019Co-Authors: Min Han, Dongdong SunAbstract:The kinase-regulatory cell signaling networks play a central role in the pathogenesis of human cervical cancer (hCC). However, only few kinase inhibitors have been successfully developed for treatment of this cancer to date. Considering that the active sites of protein kinases are highly conserved and small-molecule inhibitors should generally exhibit high promiscuity and broad specificity across the hCC-related kinase array, it is supposed that the established kinase targets of hCC can be targeted unexpectedly by certain noncognate kinase inhibitors. This provides a novel idea to practice the new uses for old drugs in anti-cancer chemotherapy. Here, we create a systematic kinase–inhibitor Binding Profile in a high-throughput manner by molecular docking and consensus scoring, where the kinases have been collected as therapeutic targets of hCC and the inhibitors are reversible, ATP-competitive and readily available. The docking/scoring scheme is tested rigorously with structure-solved and affinity-known kinase–inhibitor complex samples, which is later demonstrated to be effective in inferring unexpected inhibitor response to hCC-related kinases. Few promising kinase–inhibitor pairs are identified from the Profile and tested experimentally at cellular and molecular levels. It is found that the kinase–inhibitor promiscuity is a common phenomenon but only few can interaction effectively and inhibit potently. In addition, the high-scoring inhibitors generally exhibit good suppressing potency on hCC cell viability as compared to those low-scoring ones, imparting that the created Profile can well reflect the tumor cytotoxicity of noncognate kinase inhibitors. A further kinase assay suggests that the ErbB family kinases are the potential targets of these high-scoring inhibitors, with noncognate inhibitory activity up to nanomolar level. Structure analysis reveals that the nonbonded interactions of potent noncogante kinase–inhibitor Binding can divided into a polar tail and a nonpolar lobe, which confer specificity and stability to the Binding, respectively.
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Rational creation and systematic analysis of cervical cancer kinase-inhibitor Binding Profile.
Journal of computer-aided molecular design, 2019Co-Authors: Min Han, Dongdong SunAbstract:The kinase-regulatory cell signaling networks play a central role in the pathogenesis of human cervical cancer (hCC). However, only few kinase inhibitors have been successfully developed for treatment of this cancer to date. Considering that the active sites of protein kinases are highly conserved and small-molecule inhibitors should generally exhibit high promiscuity and broad specificity across the hCC-related kinase array, it is supposed that the established kinase targets of hCC can be targeted unexpectedly by certain noncognate kinase inhibitors. This provides a novel idea to practice the new uses for old drugs in anti-cancer chemotherapy. Here, we create a systematic kinase–inhibitor Binding Profile in a high-throughput manner by molecular docking and consensus scoring, where the kinases have been collected as therapeutic targets of hCC and the inhibitors are reversible, ATP-competitive and readily available. The docking/scoring scheme is tested rigorously with structure-solved and affinity-known kinase–inhibitor complex samples, which is later demonstrated to be effective in inferring unexpected inhibitor response to hCC-related kinases. Few promising kinase–inhibitor pairs are identified from the Profile and tested experimentally at cellular and molecular levels. It is found that the kinase–inhibitor promiscuity is a common phenomenon but only few can interaction effectively and inhibit potently. In addition, the high-scoring inhibitors generally exhibit good suppressing potency on hCC cell viability as compared to those low-scoring ones, imparting that the created Profile can well reflect the tumor cytotoxicity of noncognate kinase inhibitors. A further kinase assay suggests that the ErbB family kinases are the potential targets of these high-scoring inhibitors, with noncognate inhibitory activity up to nanomolar level. Structure analysis reveals that the nonbonded interactions of potent noncogante kinase–inhibitor Binding can divided into a polar tail and a nonpolar lobe, which confer specificity and stability to the Binding, respectively.
Rémi Quirion - One of the best experts on this subject based on the ideXlab platform.
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Differential Binding Profile and Internalization Process of Neurotensin via Neuronal and
2013Co-Authors: Glial Receptors, Dominique Nouel, Marie-pierre Faure, Jacques-andré St. Pierre, Richard Alonso, Rémi Quirion, Alain BeaudetAbstract:Two G-protein-coupled receptors for the tridecapeptide neurotensin (NT) have been identified and cloned in mammalian brain: a high-affinity (K d � 0.3 nM) receptor, sensitive to the antagonist SR 48692 but insensitive to levocabastine, and a lower-affinity (K d � 2–4 nM) receptor, sensitive to levocabastine but with poor affinity for SR 48692. Although there is good evidence that the high-affinity site is predominantly expressed in neurons, little is known of the cellular localization of the low-affinity receptor. In the present study, we identify by confocal microscopy selective levocabastine-sensitive, SR 48692resistant Binding of a fluorescent derivative of NT (fluo-NT) to a subpopulation of glial fibrillary acidic protein-immunoreactive glial cells grown in culture from the midbrain and cerebral cortex of embryonic and neonatal rats, respectively. We also demonstrate, by combining fluo-NT detection with tyrosin
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Levomepromazine receptor Binding Profile in human brain—implications for treatment—resistant schizophrenia
Acta Psychiatrica Scandinavica, 1993Co-Authors: N. P. V. Nair, D. Cecyre, Rémi QuirionAbstract:: The receptor Binding Profile of levomepromazine (LMP) in human brain was compared with that of clozapine (CLOZ) and chlorpromazine (CPZ). LMP showed significantly greater Binding affinity for both alpha-1 and serotonin-2 Binding sites than either CLOZ or CPZ, and significantly greater Binding to alpha-2 sites than CPZ. A potent pharmacological effect at these receptor sites may explain the beneficial effect of LMP on psychotic symptoms and akathisia in treatment-resistant schizophrenia recently described in 2 open studies. LMP requires further appraisal as a potentially useful neuroleptic in the management of treatment-resistant schizophrenia.
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levomepromazine receptor Binding Profile in human brain implications for treatment resistant schizophrenia
Acta Psychiatrica Scandinavica, 1993Co-Authors: N. P. V. Nair, D. Cecyre, Rémi QuirionAbstract:: The receptor Binding Profile of levomepromazine (LMP) in human brain was compared with that of clozapine (CLOZ) and chlorpromazine (CPZ). LMP showed significantly greater Binding affinity for both alpha-1 and serotonin-2 Binding sites than either CLOZ or CPZ, and significantly greater Binding to alpha-2 sites than CPZ. A potent pharmacological effect at these receptor sites may explain the beneficial effect of LMP on psychotic symptoms and akathisia in treatment-resistant schizophrenia recently described in 2 open studies. LMP requires further appraisal as a potentially useful neuroleptic in the management of treatment-resistant schizophrenia.
Min Han - One of the best experts on this subject based on the ideXlab platform.
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Rational creation and systematic analysis of cervical cancer kinase–inhibitor Binding Profile
Journal of Computer-Aided Molecular Design, 2019Co-Authors: Min Han, Dongdong SunAbstract:The kinase-regulatory cell signaling networks play a central role in the pathogenesis of human cervical cancer (hCC). However, only few kinase inhibitors have been successfully developed for treatment of this cancer to date. Considering that the active sites of protein kinases are highly conserved and small-molecule inhibitors should generally exhibit high promiscuity and broad specificity across the hCC-related kinase array, it is supposed that the established kinase targets of hCC can be targeted unexpectedly by certain noncognate kinase inhibitors. This provides a novel idea to practice the new uses for old drugs in anti-cancer chemotherapy. Here, we create a systematic kinase–inhibitor Binding Profile in a high-throughput manner by molecular docking and consensus scoring, where the kinases have been collected as therapeutic targets of hCC and the inhibitors are reversible, ATP-competitive and readily available. The docking/scoring scheme is tested rigorously with structure-solved and affinity-known kinase–inhibitor complex samples, which is later demonstrated to be effective in inferring unexpected inhibitor response to hCC-related kinases. Few promising kinase–inhibitor pairs are identified from the Profile and tested experimentally at cellular and molecular levels. It is found that the kinase–inhibitor promiscuity is a common phenomenon but only few can interaction effectively and inhibit potently. In addition, the high-scoring inhibitors generally exhibit good suppressing potency on hCC cell viability as compared to those low-scoring ones, imparting that the created Profile can well reflect the tumor cytotoxicity of noncognate kinase inhibitors. A further kinase assay suggests that the ErbB family kinases are the potential targets of these high-scoring inhibitors, with noncognate inhibitory activity up to nanomolar level. Structure analysis reveals that the nonbonded interactions of potent noncogante kinase–inhibitor Binding can divided into a polar tail and a nonpolar lobe, which confer specificity and stability to the Binding, respectively.
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Rational creation and systematic analysis of cervical cancer kinase-inhibitor Binding Profile.
Journal of computer-aided molecular design, 2019Co-Authors: Min Han, Dongdong SunAbstract:The kinase-regulatory cell signaling networks play a central role in the pathogenesis of human cervical cancer (hCC). However, only few kinase inhibitors have been successfully developed for treatment of this cancer to date. Considering that the active sites of protein kinases are highly conserved and small-molecule inhibitors should generally exhibit high promiscuity and broad specificity across the hCC-related kinase array, it is supposed that the established kinase targets of hCC can be targeted unexpectedly by certain noncognate kinase inhibitors. This provides a novel idea to practice the new uses for old drugs in anti-cancer chemotherapy. Here, we create a systematic kinase–inhibitor Binding Profile in a high-throughput manner by molecular docking and consensus scoring, where the kinases have been collected as therapeutic targets of hCC and the inhibitors are reversible, ATP-competitive and readily available. The docking/scoring scheme is tested rigorously with structure-solved and affinity-known kinase–inhibitor complex samples, which is later demonstrated to be effective in inferring unexpected inhibitor response to hCC-related kinases. Few promising kinase–inhibitor pairs are identified from the Profile and tested experimentally at cellular and molecular levels. It is found that the kinase–inhibitor promiscuity is a common phenomenon but only few can interaction effectively and inhibit potently. In addition, the high-scoring inhibitors generally exhibit good suppressing potency on hCC cell viability as compared to those low-scoring ones, imparting that the created Profile can well reflect the tumor cytotoxicity of noncognate kinase inhibitors. A further kinase assay suggests that the ErbB family kinases are the potential targets of these high-scoring inhibitors, with noncognate inhibitory activity up to nanomolar level. Structure analysis reveals that the nonbonded interactions of potent noncogante kinase–inhibitor Binding can divided into a polar tail and a nonpolar lobe, which confer specificity and stability to the Binding, respectively.
Michael J. Owens - One of the best experts on this subject based on the ideXlab platform.
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Serotonin and norepinephrine transporter Binding Profile of SSRIs.
Essential psychopharmacology, 2006Co-Authors: David A. Gutman, Michael J. OwensAbstract:Even today, pharmacotherapy for mood disorders is based almost entirely on the observation in the 1950s and 1960s that agents that enhance monoamine transmitter activity are effective antidepressants. Preclinical studies have shown that long-term administration of nearly all effective antidepressants increases the efficiency of postsynaptic serotonin transmission; many also modify central noradrenergic activity. For the majority of antidepressants, these changes are the result of their ability to block serotonin and/or norepinephrine activity at their "presynaptic uptake sites" (i.e., at the serotonin transporter [SERT] or the norepinephrine transporter [NET]). Drugs that are highly selective for one transporter over another have been demonstrated to be effective and tolerable, whereas agents that act on multiple transporters may not necessarily achieve better efficacy and may result in additional adverse events. The rationale for the use of drugs that affect multiple transports is based on the suggestion that antidepressants that block both the SERT and the NET may provide better efficacy. This can only be determined through empirical studies.
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second generation ssris human monoamine transporter Binding Profile of escitalopram and r fluoxetine
Biological Psychiatry, 2001Co-Authors: Michael J. Owens, David L Knight, Charles B. NemeroffAbstract:Abstract Background: Single isomers of the selective serotonin reuptake inhibitors citalopram (escitalopram, S -citalopram) and fluoxetine ( R -fluoxetine) are currently under development for the treatment of depression and other psychiatric disorders. Previous studies conducted in laboratory animals have revealed that the biological effects on serotonin reuptake for citalopram reside in the S enantiomer. In contrast, both enantiomers of fluoxetine contribute to its biological activity. Methods: In the present study, the potency and selectivity of escitalopram, R -fluoxetine, and all of the other currently available selective serotonin reuptake inhibitors were compared for Binding affinity at the human serotonin, norepinephrine, and dopamine transporters and several select neurotransmitter receptors using radioligand Binding assays. Results: Both escitalopram and R -fluoxetine were potent inhibitors of the serotonin transporter ( K i = 1.1 and 1.4 nmol/L, respectively). Escitalopram was the most serotonin transporter-selective compound tested and was ∼30-fold more potent than R -citalopram. Conclusions: As noted previously, paroxetine and sertraline possess moderate affinity ( R -Fluoxetine, unlike the other selective serotonin reuptake inhibitors, possesses moderate affinity ( K i = 64 nmol/L) for the serotonin 2C receptor. Potential clinical correlates of these unique attributes of escitalopram and R -fluoxetine are discussed.
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neurotransmitter receptor and transporter Binding Profile of antidepressants and their metabolites
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Michael J. Owens, W N Morgan, Susan J Plott, Charles B. NemeroffAbstract:Several new antidepressants that inhibit the serotonin (SERT) and norepinephrine transporters (NET) have been introduced into clinical practice the past several years. This report focuses on the further pharmacologic characterization of nefazodone and its metabolites within the serotonergic and noradrenergic systems, in comparison with other antidepressants. By use of radioligand Binding assays, we measured the affinity ( K i) of 13 antidepressants and 6 metabolites for the rat and human SERT and NET. The K i values for eight of the antidepressants and three metabolites were also determined for the rat 5-HT1A, 5-HT2A and muscarinic cholinergic receptors, the guinea pig histamine1 receptor and the human alpha -1 and alpha -2 receptors. These data are useful for predicting side effect Profiles and the potential for pharmacodynamic drug-drug interactions of antidepressants. Of particular interest were the findings that paroxetine, generally thought of as a selective SERT antagonist, possesses moderately high affinity for the NET and that venlafaxine, which has been described as a “dual uptake inhibitor”, possesses weak affinity for the NET. We observed significant correlations in SERT ( r = 0.965) or NET ( r = 0.983) affinity between rat and human transporters. Significant correlations were also observed between muscarinic cholinergic and NET affinity. There are several significant correlations between affinities for the 5-HT1A, 5-HT2A, histamine1, alpha -1 and alpha -2 receptors. These novel findings, not widely described previously, suggest that many of the individual drugs studied in these experiments possess some structural characteristic that determines affinity for several G protein-coupled, but not muscarinic, receptors.
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neurotransmitter receptor and transporter Binding Profile of antidepressants and their metabolites
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Michael J. Owens, W N Morgan, Susan J Plott, Charles B. NemeroffAbstract:Several new antidepressants that inhibit the serotonin (SERT) and norepinephrine transporters (NET) have been introduced into clinical practice the past several years. This report focuses on the further pharmacologic characterization of nefazodone and its metabolites within the serotonergic and noradrenergic systems, in comparison with other antidepressants. By use of radioligand Binding assays, we measured the affinity ( K i) of 13 antidepressants and 6 metabolites for the rat and human SERT and NET. The K i values for eight of the antidepressants and three metabolites were also determined for the rat 5-HT1A, 5-HT2A and muscarinic cholinergic receptors, the guinea pig histamine1 receptor and the human alpha -1 and alpha -2 receptors. These data are useful for predicting side effect Profiles and the potential for pharmacodynamic drug-drug interactions of antidepressants. Of particular interest were the findings that paroxetine, generally thought of as a selective SERT antagonist, possesses moderately high affinity for the NET and that venlafaxine, which has been described as a “dual uptake inhibitor”, possesses weak affinity for the NET. We observed significant correlations in SERT ( r = 0.965) or NET ( r = 0.983) affinity between rat and human transporters. Significant correlations were also observed between muscarinic cholinergic and NET affinity. There are several significant correlations between affinities for the 5-HT1A, 5-HT2A, histamine1, alpha -1 and alpha -2 receptors. These novel findings, not widely described previously, suggest that many of the individual drugs studied in these experiments possess some structural characteristic that determines affinity for several G protein-coupled, but not muscarinic, receptors.
Charles B. Nemeroff - One of the best experts on this subject based on the ideXlab platform.
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second generation ssris human monoamine transporter Binding Profile of escitalopram and r fluoxetine
Biological Psychiatry, 2001Co-Authors: Michael J. Owens, David L Knight, Charles B. NemeroffAbstract:Abstract Background: Single isomers of the selective serotonin reuptake inhibitors citalopram (escitalopram, S -citalopram) and fluoxetine ( R -fluoxetine) are currently under development for the treatment of depression and other psychiatric disorders. Previous studies conducted in laboratory animals have revealed that the biological effects on serotonin reuptake for citalopram reside in the S enantiomer. In contrast, both enantiomers of fluoxetine contribute to its biological activity. Methods: In the present study, the potency and selectivity of escitalopram, R -fluoxetine, and all of the other currently available selective serotonin reuptake inhibitors were compared for Binding affinity at the human serotonin, norepinephrine, and dopamine transporters and several select neurotransmitter receptors using radioligand Binding assays. Results: Both escitalopram and R -fluoxetine were potent inhibitors of the serotonin transporter ( K i = 1.1 and 1.4 nmol/L, respectively). Escitalopram was the most serotonin transporter-selective compound tested and was ∼30-fold more potent than R -citalopram. Conclusions: As noted previously, paroxetine and sertraline possess moderate affinity ( R -Fluoxetine, unlike the other selective serotonin reuptake inhibitors, possesses moderate affinity ( K i = 64 nmol/L) for the serotonin 2C receptor. Potential clinical correlates of these unique attributes of escitalopram and R -fluoxetine are discussed.
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neurotransmitter receptor and transporter Binding Profile of antidepressants and their metabolites
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Michael J. Owens, W N Morgan, Susan J Plott, Charles B. NemeroffAbstract:Several new antidepressants that inhibit the serotonin (SERT) and norepinephrine transporters (NET) have been introduced into clinical practice the past several years. This report focuses on the further pharmacologic characterization of nefazodone and its metabolites within the serotonergic and noradrenergic systems, in comparison with other antidepressants. By use of radioligand Binding assays, we measured the affinity ( K i) of 13 antidepressants and 6 metabolites for the rat and human SERT and NET. The K i values for eight of the antidepressants and three metabolites were also determined for the rat 5-HT1A, 5-HT2A and muscarinic cholinergic receptors, the guinea pig histamine1 receptor and the human alpha -1 and alpha -2 receptors. These data are useful for predicting side effect Profiles and the potential for pharmacodynamic drug-drug interactions of antidepressants. Of particular interest were the findings that paroxetine, generally thought of as a selective SERT antagonist, possesses moderately high affinity for the NET and that venlafaxine, which has been described as a “dual uptake inhibitor”, possesses weak affinity for the NET. We observed significant correlations in SERT ( r = 0.965) or NET ( r = 0.983) affinity between rat and human transporters. Significant correlations were also observed between muscarinic cholinergic and NET affinity. There are several significant correlations between affinities for the 5-HT1A, 5-HT2A, histamine1, alpha -1 and alpha -2 receptors. These novel findings, not widely described previously, suggest that many of the individual drugs studied in these experiments possess some structural characteristic that determines affinity for several G protein-coupled, but not muscarinic, receptors.
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neurotransmitter receptor and transporter Binding Profile of antidepressants and their metabolites
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Michael J. Owens, W N Morgan, Susan J Plott, Charles B. NemeroffAbstract:Several new antidepressants that inhibit the serotonin (SERT) and norepinephrine transporters (NET) have been introduced into clinical practice the past several years. This report focuses on the further pharmacologic characterization of nefazodone and its metabolites within the serotonergic and noradrenergic systems, in comparison with other antidepressants. By use of radioligand Binding assays, we measured the affinity ( K i) of 13 antidepressants and 6 metabolites for the rat and human SERT and NET. The K i values for eight of the antidepressants and three metabolites were also determined for the rat 5-HT1A, 5-HT2A and muscarinic cholinergic receptors, the guinea pig histamine1 receptor and the human alpha -1 and alpha -2 receptors. These data are useful for predicting side effect Profiles and the potential for pharmacodynamic drug-drug interactions of antidepressants. Of particular interest were the findings that paroxetine, generally thought of as a selective SERT antagonist, possesses moderately high affinity for the NET and that venlafaxine, which has been described as a “dual uptake inhibitor”, possesses weak affinity for the NET. We observed significant correlations in SERT ( r = 0.965) or NET ( r = 0.983) affinity between rat and human transporters. Significant correlations were also observed between muscarinic cholinergic and NET affinity. There are several significant correlations between affinities for the 5-HT1A, 5-HT2A, histamine1, alpha -1 and alpha -2 receptors. These novel findings, not widely described previously, suggest that many of the individual drugs studied in these experiments possess some structural characteristic that determines affinity for several G protein-coupled, but not muscarinic, receptors.