Three-dimensional recognition requirements for angiotensin agonists: A novel solution for an old problem

Gregory V. Nikiforovich, Garland R. Marshall

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)222-228
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume195
Issue number1
DOIs
StatePublished - Aug 31 1993

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