The Experts below are selected from a list of 327 Experts worldwide ranked by ideXlab platform
Nikolaus Goessweinermohr - One of the best experts on this subject based on the ideXlab platform.
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cryo em structure of pleconaril resistant rhinovirus b5 complexed to the antiviral obr 5 340 reveals unexpected binding site
Proceedings of the National Academy of Sciences of the United States of America, 2019Co-Authors: Jiri Wald, Vadim Makarov, Marion Pasin, Martina Richter, Christin Walther, Neann Mathai, Johannes Kirchmair, Nikolaus GoessweinermohrAbstract:Viral inhibitors, such as pleconaril and vapendavir, target conserved regions in the capsids of rhinoviruses (RVs) and enteroviruses (EVs) by binding to a hydrophobic pocket in viral capsid protein 1 (VP1). In resistant RVs and EVs, bulky residues in this pocket prevent their binding. However, recently developed Pyrazolopyrimidines inhibit pleconaril-resistant RVs and EVs, and computational modeling has suggested that they also bind to the hydrophobic pocket in VP1. We studied the mechanism of inhibition of pleconaril-resistant RVs using RV-B5 (1 of the 7 naturally pleconaril-resistant rhinoviruses) and OBR-5-340, a bioavailable Pyrazolopyrimidine with proven in vivo activity, and determined the 3D-structure of the protein-ligand complex to 3.6 A with cryoelectron microscopy. Our data indicate that, similar to other capsid binders, OBR-5-340 induces thermostability and inhibits viral adsorption and uncoating. However, we found that OBR-5-340 attaches closer to the entrance of the pocket than most other capsid binders, whose viral complexes have been studied so far, showing only marginal overlaps of the attachment sites. Comparing the experimentally determined 3D structure with the control, RV-B5 incubated with solvent only and determined to 3.2 A, revealed no gross conformational changes upon OBR-5-340 binding. The pocket of the naturally OBR-5-340-resistant RV-A89 likewise incubated with OBR-5-340 and solved to 2.9 A was empty. Pyrazolopyrimidines have a rigid molecular scaffold and may thus be less affected by a loss of entropy upon binding. They interact with less-conserved regions than known capsid binders. Overall, Pyrazolopyrimidines could be more suitable for the development of new, broadly active inhibitors.
Neann Mathai - One of the best experts on this subject based on the ideXlab platform.
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cryo em structure of pleconaril resistant rhinovirus b5 complexed to the antiviral obr 5 340 reveals unexpected binding site
Proceedings of the National Academy of Sciences of the United States of America, 2019Co-Authors: Jiri Wald, Vadim Makarov, Marion Pasin, Martina Richter, Christin Walther, Neann Mathai, Johannes Kirchmair, Nikolaus GoessweinermohrAbstract:Viral inhibitors, such as pleconaril and vapendavir, target conserved regions in the capsids of rhinoviruses (RVs) and enteroviruses (EVs) by binding to a hydrophobic pocket in viral capsid protein 1 (VP1). In resistant RVs and EVs, bulky residues in this pocket prevent their binding. However, recently developed Pyrazolopyrimidines inhibit pleconaril-resistant RVs and EVs, and computational modeling has suggested that they also bind to the hydrophobic pocket in VP1. We studied the mechanism of inhibition of pleconaril-resistant RVs using RV-B5 (1 of the 7 naturally pleconaril-resistant rhinoviruses) and OBR-5-340, a bioavailable Pyrazolopyrimidine with proven in vivo activity, and determined the 3D-structure of the protein-ligand complex to 3.6 A with cryoelectron microscopy. Our data indicate that, similar to other capsid binders, OBR-5-340 induces thermostability and inhibits viral adsorption and uncoating. However, we found that OBR-5-340 attaches closer to the entrance of the pocket than most other capsid binders, whose viral complexes have been studied so far, showing only marginal overlaps of the attachment sites. Comparing the experimentally determined 3D structure with the control, RV-B5 incubated with solvent only and determined to 3.2 A, revealed no gross conformational changes upon OBR-5-340 binding. The pocket of the naturally OBR-5-340-resistant RV-A89 likewise incubated with OBR-5-340 and solved to 2.9 A was empty. Pyrazolopyrimidines have a rigid molecular scaffold and may thus be less affected by a loss of entropy upon binding. They interact with less-conserved regions than known capsid binders. Overall, Pyrazolopyrimidines could be more suitable for the development of new, broadly active inhibitors.
Johannes Kirchmair - One of the best experts on this subject based on the ideXlab platform.
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cryo em structure of pleconaril resistant rhinovirus b5 complexed to the antiviral obr 5 340 reveals unexpected binding site
Proceedings of the National Academy of Sciences of the United States of America, 2019Co-Authors: Jiri Wald, Vadim Makarov, Marion Pasin, Martina Richter, Christin Walther, Neann Mathai, Johannes Kirchmair, Nikolaus GoessweinermohrAbstract:Viral inhibitors, such as pleconaril and vapendavir, target conserved regions in the capsids of rhinoviruses (RVs) and enteroviruses (EVs) by binding to a hydrophobic pocket in viral capsid protein 1 (VP1). In resistant RVs and EVs, bulky residues in this pocket prevent their binding. However, recently developed Pyrazolopyrimidines inhibit pleconaril-resistant RVs and EVs, and computational modeling has suggested that they also bind to the hydrophobic pocket in VP1. We studied the mechanism of inhibition of pleconaril-resistant RVs using RV-B5 (1 of the 7 naturally pleconaril-resistant rhinoviruses) and OBR-5-340, a bioavailable Pyrazolopyrimidine with proven in vivo activity, and determined the 3D-structure of the protein-ligand complex to 3.6 A with cryoelectron microscopy. Our data indicate that, similar to other capsid binders, OBR-5-340 induces thermostability and inhibits viral adsorption and uncoating. However, we found that OBR-5-340 attaches closer to the entrance of the pocket than most other capsid binders, whose viral complexes have been studied so far, showing only marginal overlaps of the attachment sites. Comparing the experimentally determined 3D structure with the control, RV-B5 incubated with solvent only and determined to 3.2 A, revealed no gross conformational changes upon OBR-5-340 binding. The pocket of the naturally OBR-5-340-resistant RV-A89 likewise incubated with OBR-5-340 and solved to 2.9 A was empty. Pyrazolopyrimidines have a rigid molecular scaffold and may thus be less affected by a loss of entropy upon binding. They interact with less-conserved regions than known capsid binders. Overall, Pyrazolopyrimidines could be more suitable for the development of new, broadly active inhibitors.
Daniel Rauh - One of the best experts on this subject based on the ideXlab platform.
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Characterization of Covalent Pyrazolopyrimidine–MKK7 Complexes and a Report on a Unique DFG-in/Leu-in Conformation of Mitogen-Activated Protein Kinase Kinase 7 (MKK7)
Journal of medicinal chemistry, 2019Co-Authors: Patrik Wolle, Julian Engel, Steven Smith, Lisa Goebel, Elisabeth Hennes, Jonas Lategahn, Daniel RauhAbstract:Pyrazolopyrimidines are well-established as covalent inhibitors of protein kinases such as the epidermal growth factor receptor or Bruton’s tyrosine kinase, and we recently described their potentia...
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characterization of covalent Pyrazolopyrimidine mkk7 complexes and a report on a unique dfg in leu in conformation of mitogen activated protein kinase kinase 7 mkk7
Journal of Medicinal Chemistry, 2019Co-Authors: Patrik Wolle, Julian Engel, Steven Smith, Lisa Goebel, Elisabeth Hennes, Jonas Lategahn, Daniel RauhAbstract:Pyrazolopyrimidines are well-established as covalent inhibitors of protein kinases such as the epidermal growth factor receptor or Bruton’s tyrosine kinase, and we recently described their potentia...
H. Charles Manning - One of the best experts on this subject based on the ideXlab platform.
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New structure-activity relationships of N-acetamide substituted Pyrazolopyrimidines as pharmacological ligands of TSPO.
Bioorganic & medicinal chemistry letters, 2016Co-Authors: Michael L. Schulte, Michael L. Nickels, H. Charles ManningAbstract:Translocator protein (TSPO) represents an attractive target for molecular imaging and therapy due to its prevalence and critical roles played in oncology and other pathologies. Based upon our previously optimized Pyrazolopyrimidine scaffold, we elucidated new structure activity relationships related to N,N-disubstitutions of the terminal acetamide on Pyrazolopyrimidines and further explored the impacts of these substituents on lipophilicity and plasma protein binding. Several novel chemical probes reported here exhibited significantly increased binding affinity, suitable lipophilicity and protein binding compared with contemporary TSPO ligands. We illustrate that N,N-acetamide disubstitution affords opportunities to introduce diverse chemical moieties distal to the central Pyrazolopyrimidine core, without sacrificing TSPO affinity. We anticipate that further exploration of N-acetamide substitutions may yield additional TSPO ligands capable of furthering the field of precision medicine.
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Synthesis and Structure-Activity Relationships of 5,6,7-substituted Pyrazolopyrimidines: Discovery of a novel TSPO PET Ligand for Cancer Imaging
Journal of medicinal chemistry, 2013Co-Authors: Dewei Tang, Michael L. Nickels, Eliot T. Mckinley, Matthew R. Hight, Joel M. Harp, Jason R. Buck, Uddin, H. Charles ManningAbstract:Focused library synthesis and structure-activity relationship development of 5,6,7-substituted Pyrazolopyrimidines led to the discovery of 2-(5,7-diethyl-2-(4-(2-fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide (6b), a novel translocator protein (TSPO) ligand exhibiting a 36-fold enhancement in affinity compared to another Pyrazolopyrimidine-based TSPO ligand, 6a (DPA-714). Radiolabeling with fluorine-18 ((18)F) facilitated production of 2-(5,7-diethyl-2-(4-(2-[(18)F]fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide ((18)F-6b) in high radiochemical yield and specific activity. In vivo studies of (18)F-6b were performed which illuminated this agent as an improved probe for molecular imaging of TSPO-expressing cancers.
