TY - JOUR
T1 - Three-dimensional recognition requirements for angiotensin agonists
T2 - A novel solution for an old problem
AU - Nikiforovich, Gregory V.
AU - Marshall, Garland R.
PY - 1993/8/31
Y1 - 1993/8/31
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0027170137&partnerID=8YFLogxK
U2 - 10.1006/bbrc.1993.2033
DO - 10.1006/bbrc.1993.2033
M3 - Article
C2 - 8363604
AN - SCOPUS:0027170137
SN - 0006-291X
VL - 195
SP - 222
EP - 228
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 1
ER -