Three-dimensional recognition requirements for angiotensin agonists: a novel solution for an old problem.
A novel approach involving the search for a common spatial arrangement of functionally important (pharmacophoric) groups in low-energy conformers of AT and its active analogs has been employed to determine the receptor-bound ("biologically active") conformation(s) for angiotensin II (Asp1-Arg2-Val3-Tyr4-Val/Ile5-His6-Pro7-Phe8, AT). The four pharmacophoric groups for AT are the aromatic moieties of Tyr4, His6 and Phe8 residues, as well as the C-terminal carboxyl. Geometrical comparison of the sets of low-energy backbone conformers for AT itself, and two analogs, [(alpha Me)Phe4]-AT and [Pro5]-AT, yielded the model for the receptor-bound conformation(s), which is compatible with cyclic AT analogs possessing substantial binding to specific AT receptors. A new analog, [D-Tyr4, Pro5]-AT, was designed based on the proposed receptor-bound conformation. The analog showed a good affinity (IC50 = 42.8 nM) towards specific AT receptors.
Nikiforovich
G V
GV
Center for Molecular Design, Washington University, St. Louis, MO 63130.
Marshall
G R
GR
D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000737:chemistry*; D000809:Angiotensins / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D000809:Angiotensins; D000804:Angiotensin II