Molecular Docking-Based Study of Vasopressin Analogues Modified at Positions 2 and 3 with N-Methylphenylalanine:  Influence on Receptor-Bound Conformations and Interactions with Vasopressin and Oxytocin Receptors

• Published in: Journal of medicinal chemistry 2006-04, Vol.49 (8), p.2463-2469
• Main Authors: Ślusarz, Magdalena J., Sikorska, Emilia, Ślusarz, Rafał, Ciarkowski, Jerzy
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Amino Acid Substitution; Animals; Antidiuretic Hormone Receptor Antagonists; Binding Sites - drug effects; Biological and medical sciences; Cattle; Computer Simulation; Hormones. Endocrine system; Humans; Imaging, Three-Dimensional; Ligands; Magnetic Resonance Spectroscopy; Medical sciences; Models, Chemical; Models, Molecular; Molecular Sequence Data; Pharmacology. Drug treatments; Phenylalanine - analogs & derivatives; Phenylalanine - chemistry; Protein Conformation; Protein Structure, Tertiary; Receptors, Oxytocin - antagonists & inhibitors; Receptors, Oxytocin - chemistry; Receptors, Vasopressin - chemistry; Sequence Alignment; Stereoisomerism; Structure-Activity Relationship; Vasopressins - chemistry; Vasopressins - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm051075m

In this study, four cyclic vasopressin (CYFQNCPRG-NH2, AVP) analogues substituted at positions 2 and 3 with four combinations of enantiomers of N-methylphenylalanine have been investigated. Three-dimensional structures of analogues have been formerly determined using NMR spectroscopy in dimethyl sulfoxide. Three-dimensional models of the vasopressin and oxytocin receptors were constructed by combining the multiple sequence alignment and the RD crystal structure as a template. The analogues have been docked into the receptor using the AutoDock program. The relaxation of the receptor−ligand complexes using energy minimization, followed by the constrained simulated annealing protocols (CSA), has been performed. The receptor-bound conformations of the investigated analogues have been proposed. We concluded that the N-methylated residues at positions 2 and 3 act as a structural restraint, determining the conformation of analogues, their location inside the receptor cavity, and mutual arrangement of the aromatic side chains. The conserved polar residues constitute the handles keeping the biologically active analogues inside the binding cavity. The Arg8-D2.65 salt bridge might be responsible for analogue-selective binding in OTR and V1aR versus V2R, where the positively charged K2.65 100 is present at the equivalent position.