Theoretical conformational analysis of six arginine vasopressin analogs with the L-naphthylalanine in position 3.
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 beta-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).
Slusarz
R
R
Department of Chemistry, University of Gdańsk, Poland.
Kaźmierkiewicz
R
R
Lammek
B
B
D000409:Alanine / Q000031:analogs & derivatives* / Q000737:chemistry*; D000577:Amides / Q000737:chemistry; D001127:Arginine Vasopressin / Q000737:chemistry*; D001665:Binding Sites; D006859:Hydrogen / Q000737:chemistry; D008956:Models, Chemical; D008958:Models, Molecular; D009010:Monte Carlo Method; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014867:Water / Q000378:metabolism
D000577:Amides; D014867:Water; D001127:Arginine Vasopressin; C059031:1-naphthylalanine; D006859:Hydrogen; D000409:Alanine