Modeling the adenosine receptors: comparison of the binding domains of A2A agonists and antagonists
| Autor: | Zhan-Guo Gao, Serge Van Calenbergh, Philippe Van Rompaey, Kenneth A. Jacobson, Soo-Kyung Kim, Aishe Chen, Ariel S. Gross |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Agonist
Models Molecular Adenosine A2 Receptor Agonists medicine.drug_class Stereochemistry Protein Conformation Adenosine-5'-(N-ethylcarboxamide) Ligands chemistry.chemical_compound Radioligand Assay Protein structure Drug Discovery Ribose medicine Quinazoline Animals Humans Binding site chemistry.chemical_classification Binding Sites Receptors Adenosine A2 Hydrogen Bonding Triazoles Adenosine receptor Amino acid Adenosine A2 Receptor Antagonists chemistry Docking (molecular) COS Cells Mutagenesis Site-Directed Quinazolines Molecular Medicine Hydrophobic and Hydrophilic Interactions |
| Zdroj: | Journal of medicinal chemistry. 46(23) |
| ISSN: | 0022-2623 |
| Popis: | A three-dimensional model of the human A(2A) adenosine receptor (AR) and its docked ligands was built by homology to rhodopsin and validated with site-directed mutagenesis and the synthesis of chemically complementary agonists. Different binding modes of A(2A)AR antagonists and agonists were compared by using the FlexiDock automated docking procedure, with manual adjustment. Putative binding regions for the 9H-purine ring in agonist NECA 3 and the 1H-[1,2,4]triazolo[1,5-c]quinazoline ring in antagonist CGS15943 1 overlapped, and the exocyclic amino groups of each were H-bonded to the side chain of N(6.55). For bound agonist, H-bonds formed between the ribose 3'- and 5'-substituents and the hydrophilic amino acids T(3.36), S(7.42), and H(7.43), and the terminal methyl group of the 5'-uronamide interacted with the hydrophobic side chain of F(6.44). Formation of the agonist complex destabilized the ground-state structure of the A(2A)AR, which was stabilized through a network of H-bonding and hydrophobic interactions in the transmembrane helical domain (TM) regions, facilitating a conformational change upon activation. Both flexibility of the ribose moiety, required for the movement of TM6, and its H-bonding to the receptor were important for agonism. Two sets of interhelical H-bonds involved residues conserved among ARs but not in rhodopsin: (1) E13(1.39) and H278(7.43) and (2) D52(2.50), with the highly conserved amino acids N280(7.45) and S281(7.46), and N284(7.49) with S91(3.39). Most of the amino acid residues lining the putative binding site(s) were conserved among the four AR subtypes. The A(2A)AR/3 complex showed a preference for an intermediate conformation about the glycosidic bond, unlike in the A(3)AR/3 complex, which featured an anti-conformation. Hydrophilic amino acids of TMs 3 and 7 (ribose-binding region) were replaced with anionic residues for enhanced binding to amine-derivatized agonists. We identified new neoceptor (T88D)-neoligand pairs that were consistent with the model. |
| Databáze: | OpenAIRE |
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