The Experts below are selected from a list of 149172 Experts worldwide ranked by ideXlab platform
Dennis A. Dougherty - One of the best experts on this subject based on the ideXlab platform.
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Functional Probes of Drug−Receptor Interactions Implicated by Structural Studies: Cys-Loop Receptors Provide a Fertile Testing Ground
Journal of medicinal chemistry, 2014Co-Authors: Ethan B. Van Arnam, Dennis A. DoughertyAbstract:Structures of integral membrane Receptors provide valuable models for Drug–Receptor interactions across many important classes of Drug targets and have become much more widely available in recent years. However, it remains to be determined to what extent these images are relevant to human Receptors in their biological context and how subtle issues such as subtype selectivity can be informed by them. The high precision structural modifications enabled by unnatural amino acid mutagenesis on mammalian Receptors expressed in vertebrate cells allow detailed tests of predictions from structural studies. Using the Cys-loop superfamily of ligand-gated ion channels, we show that functional studies lead to detailed binding models that, at times, are significantly at odds with the structural studies on related invertebrate proteins. Importantly, broad variations in binding interactions are seen for very closely related Receptor subtypes and for varying Drugs at a given binding site. These studies highlight the essential interplay between structural studies and functional studies that can guide efforts to develop new pharmaceuticals.
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functional probes of Drug Receptor interactions implicated by structural studies cys loop Receptors provide a fertile testing ground
Journal of Medicinal Chemistry, 2014Co-Authors: Ethan B. Van Arnam, Dennis A. DoughertyAbstract:Structures of integral membrane Receptors provide valuable models for Drug–Receptor interactions across many important classes of Drug targets and have become much more widely available in recent years. However, it remains to be determined to what extent these images are relevant to human Receptors in their biological context and how subtle issues such as subtype selectivity can be informed by them. The high precision structural modifications enabled by unnatural amino acid mutagenesis on mammalian Receptors expressed in vertebrate cells allow detailed tests of predictions from structural studies. Using the Cys-loop superfamily of ligand-gated ion channels, we show that functional studies lead to detailed binding models that, at times, are significantly at odds with the structural studies on related invertebrate proteins. Importantly, broad variations in binding interactions are seen for very closely related Receptor subtypes and for varying Drugs at a given binding site. These studies highlight the essential interplay between structural studies and functional studies that can guide efforts to develop new pharmaceuticals.
Ethan B. Van Arnam - One of the best experts on this subject based on the ideXlab platform.
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Functional Probes of Drug−Receptor Interactions Implicated by Structural Studies: Cys-Loop Receptors Provide a Fertile Testing Ground
Journal of medicinal chemistry, 2014Co-Authors: Ethan B. Van Arnam, Dennis A. DoughertyAbstract:Structures of integral membrane Receptors provide valuable models for Drug–Receptor interactions across many important classes of Drug targets and have become much more widely available in recent years. However, it remains to be determined to what extent these images are relevant to human Receptors in their biological context and how subtle issues such as subtype selectivity can be informed by them. The high precision structural modifications enabled by unnatural amino acid mutagenesis on mammalian Receptors expressed in vertebrate cells allow detailed tests of predictions from structural studies. Using the Cys-loop superfamily of ligand-gated ion channels, we show that functional studies lead to detailed binding models that, at times, are significantly at odds with the structural studies on related invertebrate proteins. Importantly, broad variations in binding interactions are seen for very closely related Receptor subtypes and for varying Drugs at a given binding site. These studies highlight the essential interplay between structural studies and functional studies that can guide efforts to develop new pharmaceuticals.
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functional probes of Drug Receptor interactions implicated by structural studies cys loop Receptors provide a fertile testing ground
Journal of Medicinal Chemistry, 2014Co-Authors: Ethan B. Van Arnam, Dennis A. DoughertyAbstract:Structures of integral membrane Receptors provide valuable models for Drug–Receptor interactions across many important classes of Drug targets and have become much more widely available in recent years. However, it remains to be determined to what extent these images are relevant to human Receptors in their biological context and how subtle issues such as subtype selectivity can be informed by them. The high precision structural modifications enabled by unnatural amino acid mutagenesis on mammalian Receptors expressed in vertebrate cells allow detailed tests of predictions from structural studies. Using the Cys-loop superfamily of ligand-gated ion channels, we show that functional studies lead to detailed binding models that, at times, are significantly at odds with the structural studies on related invertebrate proteins. Importantly, broad variations in binding interactions are seen for very closely related Receptor subtypes and for varying Drugs at a given binding site. These studies highlight the essential interplay between structural studies and functional studies that can guide efforts to develop new pharmaceuticals.
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.
Alessandro Dalpiaz - One of the best experts on this subject based on the ideXlab platform.
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binding thermodynamics as a tool to investigate the mechanisms of Drug Receptor interactions thermodynamics of cytoplasmic steroid nuclear Receptors in comparison with membrane Receptors
Journal of Medicinal Chemistry, 2005Co-Authors: Paola Gilli, Germana Gilli, And Angelo Scatturin, Katia Varani, Pier Andrea Borea, Alessandro DalpiazAbstract:Drug−Receptor binding thermodynamics has proved to be a valid tool for pharmacological and pharmaceutical characterization of molecular mechanisms of Receptor-recognition phenomena. The large number of membrane Receptors so far studied has led to the discovery of enthalpy−entropy compensation effects in Drug−Receptor binding and discrimination between agonists and antagonists by thermodynamic methods. Since a single thermodynamic study on cytoplasmic Receptors was known, this paper reports on binding thermodynamics of estradiol, ORG2058, and R1881 bound to estrogen, progesterone, and androgen steroid/nuclear Receptors, respectively, as determined by variable-temperature binding constant measurements. The binding at 25 °C appears enthalpy/entropy-driven (−53.0 ≤ ΔG° ≤ −48.6, −34.5 ≤ ΔH°≤ −19.9 kJ/mol, 0.057 ≤ ΔS° ≤ 0.111, and −2.4 ≤ ΔCp° ≤ −1.7 kJ mol-1 K-1) and is interpreted in terms of hydrophobic and hydrogen-bonded specific interactions. Results obtained for cytoplasmic Receptors are extensively compa...
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Binding thermodynamics as a tool to investigate the mechanisms of Drug-Receptor interactions: thermodynamics of cytoplasmic steroid/nuclear Receptors in comparison with membrane Receptors.
Journal of Medicinal Chemistry, 2005Co-Authors: Paola Gilli, Germana Gilli, And Angelo Scatturin, Katia Varani, Pier Andrea Borea, Alessandro DalpiazAbstract:Drug−Receptor binding thermodynamics has proved to be a valid tool for pharmacological and pharmaceutical characterization of molecular mechanisms of Receptor-recognition phenomena. The large number of membrane Receptors so far studied has led to the discovery of enthalpy−entropy compensation effects in Drug−Receptor binding and discrimination between agonists and antagonists by thermodynamic methods. Since a single thermodynamic study on cytoplasmic Receptors was known, this paper reports on binding thermodynamics of estradiol, ORG2058, and R1881 bound to estrogen, progesterone, and androgen steroid/nuclear Receptors, respectively, as determined by variable-temperature binding constant measurements. The binding at 25 °C appears enthalpy/entropy-driven (−53.0 ≤ ΔG° ≤ −48.6, −34.5 ≤ ΔH°≤ −19.9 kJ/mol, 0.057 ≤ ΔS° ≤ 0.111, and −2.4 ≤ ΔCp° ≤ −1.7 kJ mol-1 K-1) and is interpreted in terms of hydrophobic and hydrogen-bonded specific interactions. Results obtained for cytoplasmic Receptors are extensively compa...
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Binding Thermodynamics as a Tool To Investigate the Mechanisms of Drug−Receptor Interactions: Thermodynamics of Cytoplasmic Steroid/Nuclear Receptors in Comparison with Membrane Receptors
Journal of medicinal chemistry, 2005Co-Authors: Paola Gilli, Germana Gilli, And Angelo Scatturin, Katia Varani, Pier Andrea Borea, Alessandro DalpiazAbstract:Drug−Receptor binding thermodynamics has proved to be a valid tool for pharmacological and pharmaceutical characterization of molecular mechanisms of Receptor-recognition phenomena. The large number of membrane Receptors so far studied has led to the discovery of enthalpy−entropy compensation effects in Drug−Receptor binding and discrimination between agonists and antagonists by thermodynamic methods. Since a single thermodynamic study on cytoplasmic Receptors was known, this paper reports on binding thermodynamics of estradiol, ORG2058, and R1881 bound to estrogen, progesterone, and androgen steroid/nuclear Receptors, respectively, as determined by variable-temperature binding constant measurements. The binding at 25 °C appears enthalpy/entropy-driven (−53.0 ≤ ΔG° ≤ −48.6, −34.5 ≤ ΔH°≤ −19.9 kJ/mol, 0.057 ≤ ΔS° ≤ 0.111, and −2.4 ≤ ΔCp° ≤ −1.7 kJ mol-1 K-1) and is interpreted in terms of hydrophobic and hydrogen-bonded specific interactions. Results obtained for cytoplasmic Receptors are extensively compa...
Paola Gilli - One of the best experts on this subject based on the ideXlab platform.
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Binding thermodynamics as a tool to investigate the mechanisms of Drug-Receptor interactions: thermodynamics of cytoplasmic steroid/nuclear Receptors in comparison with membrane Receptors.
Journal of Medicinal Chemistry, 2005Co-Authors: Paola Gilli, Germana Gilli, And Angelo Scatturin, Katia Varani, Pier Andrea Borea, Alessandro DalpiazAbstract:Drug−Receptor binding thermodynamics has proved to be a valid tool for pharmacological and pharmaceutical characterization of molecular mechanisms of Receptor-recognition phenomena. The large number of membrane Receptors so far studied has led to the discovery of enthalpy−entropy compensation effects in Drug−Receptor binding and discrimination between agonists and antagonists by thermodynamic methods. Since a single thermodynamic study on cytoplasmic Receptors was known, this paper reports on binding thermodynamics of estradiol, ORG2058, and R1881 bound to estrogen, progesterone, and androgen steroid/nuclear Receptors, respectively, as determined by variable-temperature binding constant measurements. The binding at 25 °C appears enthalpy/entropy-driven (−53.0 ≤ ΔG° ≤ −48.6, −34.5 ≤ ΔH°≤ −19.9 kJ/mol, 0.057 ≤ ΔS° ≤ 0.111, and −2.4 ≤ ΔCp° ≤ −1.7 kJ mol-1 K-1) and is interpreted in terms of hydrophobic and hydrogen-bonded specific interactions. Results obtained for cytoplasmic Receptors are extensively compa...
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binding thermodynamics as a tool to investigate the mechanisms of Drug Receptor interactions thermodynamics of cytoplasmic steroid nuclear Receptors in comparison with membrane Receptors
Journal of Medicinal Chemistry, 2005Co-Authors: Paola Gilli, Germana Gilli, And Angelo Scatturin, Katia Varani, Pier Andrea Borea, Alessandro DalpiazAbstract:Drug−Receptor binding thermodynamics has proved to be a valid tool for pharmacological and pharmaceutical characterization of molecular mechanisms of Receptor-recognition phenomena. The large number of membrane Receptors so far studied has led to the discovery of enthalpy−entropy compensation effects in Drug−Receptor binding and discrimination between agonists and antagonists by thermodynamic methods. Since a single thermodynamic study on cytoplasmic Receptors was known, this paper reports on binding thermodynamics of estradiol, ORG2058, and R1881 bound to estrogen, progesterone, and androgen steroid/nuclear Receptors, respectively, as determined by variable-temperature binding constant measurements. The binding at 25 °C appears enthalpy/entropy-driven (−53.0 ≤ ΔG° ≤ −48.6, −34.5 ≤ ΔH°≤ −19.9 kJ/mol, 0.057 ≤ ΔS° ≤ 0.111, and −2.4 ≤ ΔCp° ≤ −1.7 kJ mol-1 K-1) and is interpreted in terms of hydrophobic and hydrogen-bonded specific interactions. Results obtained for cytoplasmic Receptors are extensively compa...
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Binding Thermodynamics as a Tool To Investigate the Mechanisms of Drug−Receptor Interactions: Thermodynamics of Cytoplasmic Steroid/Nuclear Receptors in Comparison with Membrane Receptors
Journal of medicinal chemistry, 2005Co-Authors: Paola Gilli, Germana Gilli, And Angelo Scatturin, Katia Varani, Pier Andrea Borea, Alessandro DalpiazAbstract:Drug−Receptor binding thermodynamics has proved to be a valid tool for pharmacological and pharmaceutical characterization of molecular mechanisms of Receptor-recognition phenomena. The large number of membrane Receptors so far studied has led to the discovery of enthalpy−entropy compensation effects in Drug−Receptor binding and discrimination between agonists and antagonists by thermodynamic methods. Since a single thermodynamic study on cytoplasmic Receptors was known, this paper reports on binding thermodynamics of estradiol, ORG2058, and R1881 bound to estrogen, progesterone, and androgen steroid/nuclear Receptors, respectively, as determined by variable-temperature binding constant measurements. The binding at 25 °C appears enthalpy/entropy-driven (−53.0 ≤ ΔG° ≤ −48.6, −34.5 ≤ ΔH°≤ −19.9 kJ/mol, 0.057 ≤ ΔS° ≤ 0.111, and −2.4 ≤ ΔCp° ≤ −1.7 kJ mol-1 K-1) and is interpreted in terms of hydrophobic and hydrogen-bonded specific interactions. Results obtained for cytoplasmic Receptors are extensively compa...
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enthalpy entropy compensation in Drug Receptor binding
The Journal of Physical Chemistry, 1994Co-Authors: Paola Gilli, Germana Gilli, Valeria Ferretti, Pier Andrea BoreaAbstract:The thermodynamic parameters (ΔG o , ΔH o , ΔS o ) of the Drug-Receptor binding equilibrium derived from equilibrium constant measurements at different temperatures and van't Hoff plots are reviewed. The analysis involves 186 independent experiments performed on 136 ligands binding to 10 biological Receptors and, for comparison, to DNA and to two different enzymes. ΔH o and ΔS o values correlate according to the regression equation ΔH o (kcal mol -1 )=-9.5+27845 o (kcal K -1 mol -1 ) with a correlation coefficient of 0.981. The correlating equation is of the form ΔH o =βΔS o and is expected for a case of enthalpy-entropy compensation with a compensation temperature β=278 K
