Theoretical conformational analysis of six arginine vasopressin analogs with the l-naphthylalanine in position 3

• Published in: The journal of peptide research 2000-12, Vol.56 (6), p.352-359
• Main Authors: Ślusarz, R., Kaźmierkiewicz, R., Lammek, B.
• Format: Article
• Language: English
• Subjects: Alanine - analogs & derivatives; Alanine - chemistry; Amides - chemistry; Arginine Vasopressin - chemistry; Binding Sites; conformational energy calculations; ECEPP/3 force field; effect of hydration on conformation; Hydrogen - chemistry; Models, Chemical; Models, Molecular; Monte Carlo Method; Protein Conformation; Structure-Activity Relationship; vasopressin antagonists; Water - metabolism
• ISSN: 1397-002X; 1399-3011
• DOI: 10.1034/j.1399-3011.2000.00743.x

: Introduction of the naphthylalanine residue into either position 3 of arginine vasopressin (AVP), or its analogs results in peptides with interesting pharmacological properties. The single substituted analog of AVP with l‐2‐Nal in position 3 causes moderate antiduretic activity, whereas [Mpa1, (l‐1‐Nal)3, (d‐Arg)8] VP and [Mpa1, (l‐2‐Nal)3, (d‐Arg)8] VP are potent and selective V2 agonists. Moreover [(l‐2‐Nal)3, (d‐Arg)8] VP is among the most potent and selective antagonists of V1a receptors. In this study we carried out conformational calculations on [(l‐1‐Nal)3] AVP, [(l‐2‐Nal)3] AVP, [(l‐1‐Nal)3, (d‐Arg)8] VP, [(l‐2‐Nal)3, (d‐Arg)8] VP, [Mpa1, (l‐1‐Nal)3, (d‐Arg)8] VP, [Mpa1, (l‐2‐Nal)3, (d‐Arg)8] VP, using the ECEPP/3 force field with and without including hydration to simulate aqueous and nonpolar environments. It was found that in all six compound studied, the low‐energy conformations have common geometry and relative energies. Therefore, the modifications of the Phe in position 3 influence the binding to the receptor by changing the size of the third residue, rather than by changing the conformational space. The lowest‐energy conformations in the presence and absence of water had β‐turns at residues Phe3‐Gln4 and Gln4‐Asn5 and Gln4‐Asn5, respectively. The conformation at the Gln4‐Asn5 turn was most similar to the crystal structure of the pressinoic acid (the cyclic moiety of vasopressin).