Determination of the binding mode and interacting amino-acids for dibasic H3 receptor antagonists
| Autor: | Isabelle Berrebi-Bertrand, Olivier Labeeuw, Thierry Calmels, Jean-Charles Schwartz, Olivia Poupardin-Olivier, Marc Capet, Nicolas Levoin, Stéphane Krief, Jeanne-Marie Lecomte |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Models
Molecular Stereochemistry Clinical Biochemistry Molecular Sequence Data Histamine Antagonists Molecular Conformation Pharmaceutical Science Plasma protein binding Ligands Biochemistry Drug Discovery Receptors Histamine H3 Amino Acid Sequence Amino Acids Molecular Biology Peptide sequence G protein-coupled receptor chemistry.chemical_classification Drug discovery Chemistry Organic Chemistry Ligand (biochemistry) Amino acid Transmembrane domain Docking (molecular) Drug Design Molecular Medicine Protein Binding |
| Zdroj: | Bioorganicmedicinal chemistry. 21(15) |
| ISSN: | 1464-3391 |
| Popis: | Due to its involvement in major CNS functions, the histamine H3 receptor (H3R) is the subject of intensive medicinal chemistry investigation, supported by the range of modern drug discovery tools, such as receptor modeling and ligand docking. Although the receptor models described to date share a majority of common traits, they display discrete alternatives in amino-acid conformation, rendering ligand binding modes quite different. Such variations impede structure-based drug design in the H3R field. In the present study, we used a combination of medicinal chemistry, receptor-guided and ligand-based methods to elucidate the binding mode of antagonists. The approaches converged towards a ligand orientation perpendicular to the membrane plane, bridging Glu206 of the transmembrane helix 5 to acidic amino acids of the extracellular loops. This consensus will help future structure-based drug design for H3R ligands. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect