Recognition of Privileged Structures by G-Protein Coupled Receptors
| العنوان: | Recognition of Privileged Structures by G-Protein Coupled Receptors |
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| المؤلفون: | Kent Bondensgaard, Henning Thøgersen, Birgitte Schjellerup Wulff, Robert P. Bywater, Birgit Sehested Hansen, Michael Ankersen |
| المصدر: | Journal of Medicinal Chemistry. 47:888-899 |
| بيانات النشر: | American Chemical Society (ACS), 2004. |
| سنة النشر: | 2004 |
| مصطلحات موضوعية: | Models, Molecular, Indoles, Stereochemistry, Molecular Sequence Data, Tetrazoles, Sequence alignment, Ligands, Receptor, Angiotensin, Type 1, Cell Line, Receptors, G-Protein-Coupled, Conserved sequence, Turn (biochemistry), Molecular recognition, Piperidines, Cricetinae, Drug Discovery, Animals, Spiro Compounds, Amino Acid Sequence, Binding site, Receptors, Ghrelin, Conserved Sequence, G protein-coupled receptor, Binding Sites, Chemistry, Biphenyl Compounds, Ligand (biochemistry), Biphenyl compound, Receptors, Serotonin, Indans, Receptor, Melanocortin, Type 4, Molecular Medicine, Sequence Alignment |
| الوصف: | Privileged structures are ligand substructures that are widely used to generate high-affinity ligands for more than one type of receptor. To explain this, we surmised that there must be some common feature in the target proteins. For a set of class A GPCRs, we found a good correlation between conservation patterns of residues in the ligand binding pocket and the privileged structure fragments in class A GPCR ligands. A major part of interior surface of the common ligand binding pocket of class A receptors, identified in many GPCRs, is lined with variable residues that are responsible for selectivity in ligand recognition, while other regions, typically located deeper into the binding pocket, are more conserved and retain a predominantly hydrophobic and aromatic character. The latter is reflected in the chemical nature of most GPCR privileged structures and is proposed to be the common feature that is recognized by the privileged structures. Further, we find that this subpocket is conserved even in distant orthologs within the class A family. Three pairs of ligands recognizing widely different receptor types were docked into receptor models of their target receptors utilizing available structure- activity relationships and mutagenesis data. For each pair of ligands, the ligand-receptor complexes reveal that the nature of the privileged structure binding pocket is conserved between the two complexes, in support of our hypothesis. Only part of the privileged structures can be accommodated within the conserved subpocket. Some contacts are established between the privileged structure and the nonconserved parts of the binding pocket. This implies that any one particular privileged structure can target only a subset of receptors, those complementary to the full privileged structure. Our hypothesis leads to a valuable novelty in that ligand libraries can be designed without any foreknowledge of the structure of the endogenous ligand, which in turn means that even orphan receptors can in principle now be addressed as potential drug targets. |
| تدمد: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm0309452 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9080a39b78a525510867fae72ff47fc2 https://doi.org/10.1021/jm0309452 |
| رقم الانضمام: | edsair.doi.dedup.....9080a39b78a525510867fae72ff47fc2 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15204804 00222623 |
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| DOI: | 10.1021/jm0309452 |