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David E Shaw - One of the best experts on this subject based on the ideXlab platform.
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molecular determinants of drug Receptor Binding kinetics
Drug Discovery Today, 2013Co-Authors: David W Borhani, David E Shaw, Ron O DrorAbstract:It is increasingly appreciated that the rates at which drugs associate with and dissociate from Receptors — the Binding kinetics — directly impact drug efficacy and safety. The molecular determinants of drug–Receptor Binding kinetics remain poorly understood, however, especially when compared with the well-known factors that affect Binding affinity. The rational modulation of kinetics during lead optimization thus remains challenging. We review some of the key factors thought to control drug–Receptor Binding kinetics at the molecular level — molecular size, conformational fluctuations, electrostatic interactions and hydrophobic effects — and discuss several possible approaches for the rational design of drugs with desired Binding kinetics.
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Molecular determinants of drug–Receptor Binding kinetics
Drug Discovery Today, 2013Co-Authors: David W Borhani, Ron O Dror, David E ShawAbstract:It is increasingly appreciated that the rates at which drugs associate with and dissociate from Receptors — the Binding kinetics — directly impact drug efficacy and safety. The molecular determinants of drug–Receptor Binding kinetics remain poorly understood, however, especially when compared with the well-known factors that affect Binding affinity. The rational modulation of kinetics during lead optimization thus remains challenging. We review some of the key factors thought to control drug–Receptor Binding kinetics at the molecular level — molecular size, conformational fluctuations, electrostatic interactions and hydrophobic effects — and discuss several possible approaches for the rational design of drugs with desired Binding kinetics.
Jesse D. Bloom - One of the best experts on this subject based on the ideXlab platform.
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antibody neutralization of an influenza virus that uses neuraminidase for Receptor Binding
Viruses, 2020Co-Authors: Lauren Gentles, Maryna C Eichelberger, Jesse D. BloomAbstract:Influenza virus infection elicits antibodies against the Receptor-Binding protein hemagglutinin (HA) and the Receptor-cleaving protein neuraminidase (NA). Because HA is essential for viral entry, antibodies targeting HA often potently neutralize the virus in single-cycle infection assays. However, antibodies against NA are not potently neutralizing in such assays, since NA is dispensable for single-cycle infection. Here we show that a modified influenza virus that depends on NA for Receptor Binding is much more sensitive than a virus with Receptor-Binding HA to neutralization by some anti-NA antibodies. Specifically, a virus with a Receptor-Binding G147R N1 NA and a Binding-deficient HA is completely neutralized in single-cycle infections by an antibody that binds near the NA active site. Infection is also substantially inhibited by antibodies that bind NA epitopes distant from the active site. Finally, we demonstrate that this modified virus can be used to efficiently select mutations in NA that escape antibody Binding, a task that can be laborious with typical influenza viruses that are not well neutralized by anti-NA antibodies. Thus, viruses dependent on NA for Receptor Binding allow for sensitive in vitro detection of antibodies Binding near the catalytic site of NA and enable the selection of viral escape mutants.
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antibody neutralization of an influenza virus that uses neuraminidase for Receptor Binding
bioRxiv, 2020Co-Authors: Lauren Gentles, Maryna C Eichelberger, Jesse D. BloomAbstract:Influenza virus infection elicits antibodies against the Receptor-Binding protein hemagglutinin (HA) and the Receptor-cleaving protein neuraminidase (NA). Because HA is essential for viral entry, antibodies targeting HA often potently neutralize the virus in single-cycle infection assays. But antibodies against NA are not potently neutralizing in such assays, since NA is dispensable for single-cycle infection. Here we show that a modified influenza virus that depends on NA for Receptor Binding is much more sensitive than a virus with Receptor-Binding HA to neutralization by some anti-NA antibodies. Specifically, virus with a Receptor-Binding G147R N1 NA and a Binding-deficient HA is completely neutralized in single-cycle infections by an antibody that binds near the NA active site. Infection is also substantially inhibited by antibodies that bind NA epitopes distant from the active site. Finally, we demonstrate that this modified virus can be used to efficiently select mutations in NA that escape antibody Binding, a task that can be laborious with typical influenza viruses that are not well-neutralized by anti-NA antibodies. Thus, viruses dependent on NA for Receptor Binding allow for sensitive in vitro detection of antibodies Binding near the catalytic site of NA and enable selection of viral escape mutants.
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A mutant influenza virus that uses an N1 neuraminidase as the Receptor-Binding protein
Journal of virology, 2013Co-Authors: Kathryn A. Hooper, Jesse D. BloomAbstract:In the vast majority of influenza A viruses characterized to date, hemagglutinin (HA) is the Receptor-Binding and fusion protein, whereas neuraminidase (NA) is a Receptor-cleaving protein that facilitates viral release but is expendable for entry. However, the NAs of some recent human H3N2 isolates have acquired Receptor-Binding activity via the mutation D151G, although these isolates also appear to retain the ability to bind Receptors via HA. We report here the laboratory generation of a mutation (G147R) that enables an N1 NA to completely co-opt the Receptor-Binding function normally performed by HA. Viruses with this mutant NA grow to high titers even in the presence of extensive mutations to conserved residues in HA's Receptor-Binding pocket. When the Receptor-Binding NA is paired with this Binding-deficient HA, viral infectivity and red blood cell agglutination are blocked by NA inhibitors. Furthermore, virus-like particles expressing only the Receptor-Binding NA agglutinate red blood cells in an NA-dependent manner. Although the G147R NA Receptor-Binding mutant virus that we characterize is a laboratory creation, this same mutation is found in several natural clusters of H1N1 and H5N1 viruses. Our results demonstrate that, at least in tissue culture, influenza virus Receptor-Binding activity can be entirely shifted from HA to NA.
Richard D. Howells - One of the best experts on this subject based on the ideXlab platform.
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Studies on Inhibition of and Opioid Receptor Binding by Dithiothreitol and N-Ethylmaleimide His IS CRITICAL FOR μ OPIOID Receptor Binding AND INACTIVATION BY N-ETHYLMALEIMIDE
Journal of Biological Chemistry, 1996Co-Authors: Mandana Shahrestanifar, William W. Wang, Richard D. HowellsAbstract:Abstract The sensitivity of μ and Receptor Binding to dithiothreitol and N-ethylmaleimide was examined to probe Receptor structure and function. Binding to both Receptor types was inhibited by dithiothreitol (IC values = 250 mM), suggesting the presence of inaccessible but critical disulfide linkages. μ Receptor Binding was inhibited with more rapid kinetics and at lower N-ethylmaleimide concentrations than Receptor Binding. Ligand protection against N-ethylmaleimide inactivation suggested that alkylation was occurring within, or in the vicinity of, the Receptor Binding pocket. Sodium ions dramatically affected the IC of N-ethylmaleimide toward both Receptor types in a ligand-dependent manner. Analysis of Receptor chimeras suggested that the site of N-ethylmaleimide alkylation on the μ Receptor was between transmembrane domains 3 and 5. Substitution of cysteines between transmembrane domains 3 and 5 and elsewhere had no effect on Receptor Binding or sensitivity toward N-ethylmaleimide. Serine substitution of His in the putative second extracellular loop linking transmembrane domains 4 and 5 protected against N-ethylmaleimide inactivation. The H223S substitution decreased the affinity of bremazocine 25-fold, highlighting the importance of this residue for the formation of the high affinity bremazocine Binding site in the μ opioid Receptor.
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Studies on inhibition of mu and delta opioid Receptor Binding by dithiothreitol and N-ethylmaleimide. His223 is critical for mu opioid Receptor Binding and inactivation by N-ethylmaleimide.
The Journal of biological chemistry, 1996Co-Authors: Mandana Shahrestanifar, William W. Wang, Richard D. HowellsAbstract:The sensitivity of mu and delta Receptor Binding to dithiothreitol and N-ethylmaleimide was examined to probe Receptor structure and function. Binding to both Receptor types was inhibited by dithiothreitol (IC50 values = 250 mM), suggesting the presence of inaccessible but critical disulfide linkages. mu Receptor Binding was inhibited with more rapid kinetics and at lower N-ethylmaleimide concentrations than delta Receptor Binding. Ligand protection against N-ethylmaleimide inactivation suggested that alkylation was occurring within, or in the vicinity of, the Receptor Binding pocket. Sodium ions dramatically affected the IC50 of N-ethylmaleimide toward both Receptor types in a ligand-dependent manner. Analysis of Receptor chimeras suggested that the site of N-ethylmaleimide alkylation on the mu Receptor was between transmembrane domains 3 and 5. Substitution of cysteines between transmembrane domains 3 and 5 and elsewhere had no effect on Receptor Binding or sensitivity toward N-ethylmaleimide. Serine substitution of His223 in the putative second extracellular loop linking transmembrane domains 4 and 5 protected against N-ethylmaleimide inactivation. The H223S substitution decreased the affinity of bremazocine 25-fold, highlighting the importance of this residue for the formation of the high affinity bremazocine Binding site in the mu opioid Receptor.
David W Borhani - One of the best experts on this subject based on the ideXlab platform.
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molecular determinants of drug Receptor Binding kinetics
Drug Discovery Today, 2013Co-Authors: David W Borhani, David E Shaw, Ron O DrorAbstract:It is increasingly appreciated that the rates at which drugs associate with and dissociate from Receptors — the Binding kinetics — directly impact drug efficacy and safety. The molecular determinants of drug–Receptor Binding kinetics remain poorly understood, however, especially when compared with the well-known factors that affect Binding affinity. The rational modulation of kinetics during lead optimization thus remains challenging. We review some of the key factors thought to control drug–Receptor Binding kinetics at the molecular level — molecular size, conformational fluctuations, electrostatic interactions and hydrophobic effects — and discuss several possible approaches for the rational design of drugs with desired Binding kinetics.
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Molecular determinants of drug–Receptor Binding kinetics
Drug Discovery Today, 2013Co-Authors: David W Borhani, Ron O Dror, David E ShawAbstract:It is increasingly appreciated that the rates at which drugs associate with and dissociate from Receptors — the Binding kinetics — directly impact drug efficacy and safety. The molecular determinants of drug–Receptor Binding kinetics remain poorly understood, however, especially when compared with the well-known factors that affect Binding affinity. The rational modulation of kinetics during lead optimization thus remains challenging. We review some of the key factors thought to control drug–Receptor Binding kinetics at the molecular level — molecular size, conformational fluctuations, electrostatic interactions and hydrophobic effects — and discuss several possible approaches for the rational design of drugs with desired Binding kinetics.
Mandana Shahrestanifar - One of the best experts on this subject based on the ideXlab platform.
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Studies on Inhibition of and Opioid Receptor Binding by Dithiothreitol and N-Ethylmaleimide His IS CRITICAL FOR μ OPIOID Receptor Binding AND INACTIVATION BY N-ETHYLMALEIMIDE
Journal of Biological Chemistry, 1996Co-Authors: Mandana Shahrestanifar, William W. Wang, Richard D. HowellsAbstract:Abstract The sensitivity of μ and Receptor Binding to dithiothreitol and N-ethylmaleimide was examined to probe Receptor structure and function. Binding to both Receptor types was inhibited by dithiothreitol (IC values = 250 mM), suggesting the presence of inaccessible but critical disulfide linkages. μ Receptor Binding was inhibited with more rapid kinetics and at lower N-ethylmaleimide concentrations than Receptor Binding. Ligand protection against N-ethylmaleimide inactivation suggested that alkylation was occurring within, or in the vicinity of, the Receptor Binding pocket. Sodium ions dramatically affected the IC of N-ethylmaleimide toward both Receptor types in a ligand-dependent manner. Analysis of Receptor chimeras suggested that the site of N-ethylmaleimide alkylation on the μ Receptor was between transmembrane domains 3 and 5. Substitution of cysteines between transmembrane domains 3 and 5 and elsewhere had no effect on Receptor Binding or sensitivity toward N-ethylmaleimide. Serine substitution of His in the putative second extracellular loop linking transmembrane domains 4 and 5 protected against N-ethylmaleimide inactivation. The H223S substitution decreased the affinity of bremazocine 25-fold, highlighting the importance of this residue for the formation of the high affinity bremazocine Binding site in the μ opioid Receptor.
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Studies on inhibition of mu and delta opioid Receptor Binding by dithiothreitol and N-ethylmaleimide. His223 is critical for mu opioid Receptor Binding and inactivation by N-ethylmaleimide.
The Journal of biological chemistry, 1996Co-Authors: Mandana Shahrestanifar, William W. Wang, Richard D. HowellsAbstract:The sensitivity of mu and delta Receptor Binding to dithiothreitol and N-ethylmaleimide was examined to probe Receptor structure and function. Binding to both Receptor types was inhibited by dithiothreitol (IC50 values = 250 mM), suggesting the presence of inaccessible but critical disulfide linkages. mu Receptor Binding was inhibited with more rapid kinetics and at lower N-ethylmaleimide concentrations than delta Receptor Binding. Ligand protection against N-ethylmaleimide inactivation suggested that alkylation was occurring within, or in the vicinity of, the Receptor Binding pocket. Sodium ions dramatically affected the IC50 of N-ethylmaleimide toward both Receptor types in a ligand-dependent manner. Analysis of Receptor chimeras suggested that the site of N-ethylmaleimide alkylation on the mu Receptor was between transmembrane domains 3 and 5. Substitution of cysteines between transmembrane domains 3 and 5 and elsewhere had no effect on Receptor Binding or sensitivity toward N-ethylmaleimide. Serine substitution of His223 in the putative second extracellular loop linking transmembrane domains 4 and 5 protected against N-ethylmaleimide inactivation. The H223S substitution decreased the affinity of bremazocine 25-fold, highlighting the importance of this residue for the formation of the high affinity bremazocine Binding site in the mu opioid Receptor.
