Derivation of a 3D pharmacophore model for the angiotensin-II site one receptor |
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| Authors: | Kristine Prendergast Kym Adams William J. Greenlee Robert B. Nachbar Arthur A. Patchett Dennis J. Underwood |
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| Affiliation: | (1) Molecular Systems Department, Merck Research Laboratories, P.O. Box 2000, 07065 Rahway, NJ, U.S.A.;(2) Department of Exploratory Chemistry, Merck Research Laboratories, P.O. Box 2000, 07065 Rahway, NJ, U.S.A. |
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| Abstract: | Summary 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. |
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| Keywords: | Computer-aided design CoMFA Conformational generation Pharmacophore mapping Systematic search |
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