Derivation of a 3D pharmacophore model for the angiotensin-II site one receptor.
A systematic search has been used to derive a hypothesis for the receptor-bound conformation of A-II antagonists at the AT1 receptor. The validity of the pharmacophore hypothesis has been tested using CoMFA, which included 50 diverse A-II antagonists, spanning four orders of magnitude in activity. The resulting cross-validated R2 of 0.64 (conventional R2 of 0.76) is indicative of a good predictive model of activity, and has been used to estimate potency for a variety of non-peptidyl antagonists. The structural model for the non-peptide has been compared with respect to the natural substrate, A-II, by generating peptide to non-peptide overlays.
Prendergast
K
K
Molecular Systems Department, Merck Research Laboratories, Rahway, NJ 07065.
Adams
K
K
Greenlee
W J
WJ
Nachbar
R B
RB
Patchett
A A
AA
Underwood
D J
DJ
D000804:Angiotensin II / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D001665:Binding Sites; D017076:Computer-Aided Design; D015195:Drug Design; D004563:Electrochemistry; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011945:Receptors, Angiotensin / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000737:chemistry / Q000494:pharmacology; D013816:Thermodynamics
D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; C070967:L 158809