Theoretical conformational analysis of three vasopressin antagonists with a modified cyclohexyl ring in the first thioacid residue.
Analogues of arginine vasopressin (AVP) with bulky thioacid residues in position 1 of the amino acid sequence are known to be effective antagonists of the pressor response. Some of the most effective ones are those that have the first cysteine residue replaced with beta,beta-cyclopentamethylene-beta'-mercaptopropionic acid (Cpp) and its derivatives, such as 4-mercapto-4-tetrahydropyraneacetic acid (OCA) and 4-mercapto-4-tetrahydrothiopyraneacetic acid (SCA). The SCA analogues are more potent and the OCA ones slightly less potent antagonists than the Cpp ones. In this study we carried out conformational calculations on [Cpp1]AVP, [OCA1]AVP and [SCA1]AVP, using the ECEPP/3 force field both with and without hydration (to simulate an aqueous and non-polar receptor environment, respectively). It was found that most of the low-energy conformations are common in geometry and relative energy for all three compounds studied. It can therefore be concluded that the modifications of the cyclohexyl ring in position 1 influence the binding to the receptor because of changing the lipophilicity of the first residue, rather than by changing the conformational space. This is further supported by the fact that the lowest-energy conformations in the absence of water have closely located the Phe3 side chain (which is critical for the interaction with vasopressin receptors) and the (modified) cyclohexyl ring. 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 with the turn at Gln4-Asn5 was most similar to the crystal structure of the pressinoic acid (the cyclic moiety of vasopressin).
Kaźmierkiewicz
R
R
Department of Chemistry, University of Gdańsk, Poland.
Liwo
A
A
Lammek
B
B
D001127:Arginine Vasopressin / Q000031:analogs & derivatives* / Q000737:chemistry*; D003511:Cyclohexanols; D008958:Models, Molecular; D009010:Monte Carlo Method; D011422:Propionates; D011487:Protein Conformation; D014667:Vasopressins / Q000037:antagonists & inhibitors*
D003511:Cyclohexanols; D011422:Propionates; D014667:Vasopressins; D001127:Arginine Vasopressin