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”) conformations(s) for angiotensin II (Asp¹-Arg²-Val³-Tyr⁴-Val/Ile⁵-His⁶-Pro⁷-Phe⁸, AT). The four pharmacophoric groups for AT are the aromatic moieties for 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, [(αMe)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.