MOLECULAR MODELING OF THE VASOPRESSIN V2 RECEPTOR ANTAGONIST INTERACTIONS/

We predict some essential interactions between the V2 vasopressin rena l receptor (V2R) and its selective peptide antagonist desGly(9)-[Mca(1 ),D-Ile(2),Ile(4)]AVP, and compare these predictions with the earlier ones for the non-peptide OPC-36120 antagonist-and the [Arg(8)]vasopres sin (AVP) agonist-V2 receptor interactions. V2R controls antidiuresis in mammals and belongs to the superfamily of the heptahelical transmem brane (7TM) G protein-coupled receptors (GPCR)s. V2R was built, the li gands docked and the structures relaxed using advanced molecular model ing techniques. Both the agonist and the antagonists (no matter whethe r of peptide- or non-peptide type) appear to prefer a common V2R compa rtment for docking. The receptor aminoacid residues, potentially impor tant in ligand binding, are mainly in the TM3-TM7 helices. A few of th ese residues are invariant for the whole GPCR superfamily while most o f them are conserved in the subfamily of neurohypophyseal receptors, t o which V2R belongs. Some of the equivalent residues in a related V1a receptor have been earlier reported as critical for the ligand affinit y.