Evaluation of Small-Molecule Modulators of the Luteinizing Hormone/Choriogonadotropin and Thyroid Stimulating Hormone Receptors: Structure−Activity Relationships and Selective Binding Patterns
Susanna MooreChemical Biology Core Facility, Clinical Endocrinology Branch, and Computational Chemistry Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, III Department of Medicine, University of Leipzig, D-04103 Leipzig, Germany, and Structural Bioinformatics and Molecular Design, Leibniz-Institut für Molekulare Pharmakologie, D-13125 Berlin, GermanyHolger JaeschkeChemical Biology Core Facility, Clinical Endocrinology Branch, and Computational Chemistry Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, III Department of Medicine, University of Leipzig, D-04103 Leipzig, Germany, and Structural Bioinformatics and Molecular Design, Leibniz-Institut für Molekulare Pharmakologie, D-13125 Berlin, GermanyGunnar KleinauChemical Biology Core Facility, Clinical Endocrinology Branch, and Computational Chemistry Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, III Department of Medicine, University of Leipzig, D-04103 Leipzig, Germany, and Structural Bioinformatics and Molecular Design, Leibniz-Institut für Molekulare Pharmakologie, D-13125 Berlin, GermanySusanne NeumannChemical Biology Core Facility, Clinical Endocrinology Branch, and Computational Chemistry Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, III Department of Medicine, University of Leipzig, D-04103 Leipzig, Germany, and Structural Bioinformatics and Molecular Design, Leibniz-Institut für Molekulare Pharmakologie, D-13125 Berlin, GermanyStefano CostanziChemical Biology Core Facility, Clinical Endocrinology Branch, and Computational Chemistry Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, III Department of Medicine, University of Leipzig, D-04103 Leipzig, Germany, and Structural Bioinformatics and Molecular Design, Leibniz-Institut für Molekulare Pharmakologie, D-13125 Berlin, GermanyJian‐kang JiangChemical Biology Core Facility, Clinical Endocrinology Branch, and Computational Chemistry Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, III Department of Medicine, University of Leipzig, D-04103 Leipzig, Germany, and Structural Bioinformatics and Molecular Design, Leibniz-Institut für Molekulare Pharmakologie, D-13125 Berlin, GermanyJohn ChildressChemical Biology Core Facility, Clinical Endocrinology Branch, and Computational Chemistry Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, III Department of Medicine, University of Leipzig, D-04103 Leipzig, Germany, and Structural Bioinformatics and Molecular Design, Leibniz-Institut für Molekulare Pharmakologie, D-13125 Berlin, GermanyBruce M. RaakaChemical Biology Core Facility, Clinical Endocrinology Branch, and Computational Chemistry Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, III Department of Medicine, University of Leipzig, D-04103 Leipzig, Germany, and Structural Bioinformatics and Molecular Design, Leibniz-Institut für Molekulare Pharmakologie, D-13125 Berlin, GermanyAnny Odile ColsonChemical Biology Core Facility, Clinical Endocrinology Branch, and Computational Chemistry Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, III Department of Medicine, University of Leipzig, D-04103 Leipzig, Germany, and Structural Bioinformatics and Molecular Design, Leibniz-Institut für Molekulare Pharmakologie, D-13125 Berlin, GermanyRalf PaschkeChemical Biology Core Facility, Clinical Endocrinology Branch, and Computational Chemistry Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, III Department of Medicine, University of Leipzig, D-04103 Leipzig, Germany, and Structural Bioinformatics and Molecular Design, Leibniz-Institut für Molekulare Pharmakologie, D-13125 Berlin, GermanyGerd KrauseChemical Biology Core Facility, Clinical Endocrinology Branch, and Computational Chemistry Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, III Department of Medicine, University of Leipzig, D-04103 Leipzig, Germany, and Structural Bioinformatics and Molecular Design, Leibniz-Institut für Molekulare Pharmakologie, D-13125 Berlin, GermanyCraig J. ThomasChemical Biology Core Facility, Clinical Endocrinology Branch, and Computational Chemistry Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, III Department of Medicine, University of Leipzig, D-04103 Leipzig, Germany, and Structural Bioinformatics and Molecular Design, Leibniz-Institut für Molekulare Pharmakologie, D-13125 Berlin, GermanyMarvin C. GershengornChemical Biology Core Facility, Clinical Endocrinology Branch, and Computational Chemistry Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, III Department of Medicine, University of Leipzig, D-04103 Leipzig, Germany, and Structural Bioinformatics and Molecular Design, Leibniz-Institut für Molekulare Pharmakologie, D-13125 Berlin, Germany
2006en
ABI
Abstract
The substituted thieno[2,3-d]pyrimidine 3 (Org 41841), a partial agonist for the luteinizing hormone/choriogonadotropin receptor (LHCGR) and the closely related thyroid-stimulating hormone receptor (TSHR), was fundamentally altered, and the resulting analogues were analyzed for their potencies, efficacies, and specificities at LHCGR and TSHR. Chemical modification of the parent compound combined with prior mutagenesis of TSHR provided compelling experimental evidence in support of computational models of 3 binding to TSHR and LHCGR within their transmembrane cores. Biochemical analysis of a specific modification to the chemical structure of 3 provides additional evidence of a H-bond between the ligand and a glutamate residue in transmembrane helix 3, which is conserved in both receptors. Several key interactions were surveyed to determine their respective biochemical roles in terms of both van der Waals dimensions and hydrogen bond capacity and the respective relationship to biological activity.
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Citations and references
Cited by 30 references