Conformation-function relationship of vitamin D: conformational analysis predicts potential side-chain structure

Journal of Medicinal Chemistry
S YamadaM Ohta

Abstract

In previous studies, we have grouped regions in space occupied by the vitamin D side chain into four: A, G, EA, and EG. We showed that the receptor (VDR) affinity of 1alpha,25-dihydroxyvitamin D3 derivatives increases, in terms of side-chain region, in the order EG, G, A, and EA. We called this the active space group concept. In the present study, we used this active space group concept to analyze the conformation-activity relationship of about 40 representative potent 1alpha,25-dihydroxyvitamin D3 analogues. We initially listed structural modifications in the side chain of potent vitamin D analogues and estimated their potency factor. Possible side-chain conformations of representative analogues were calculated by the molecular mechanics method and plotted on a dot map compared with the regions A, G, EA, and EG. The cell-differentiating potency of the analogues was correlated with our active space group concept with few exceptions. Among potent analogues with a natural configuration at C(20), the side chains of those with a 22-oxa, 22-ene, 16-ene, or a 18-nor modification were located in front of region EA (termed F). The side chains of the most potent 20-epi-22-oxa-24-homovitamin D analogues were concentrated at the left side...Continue Reading

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Citations

Nov 9, 2002·Medicinal Research Reviews·Sachiko YamadaKeiko Yamamoto
Apr 28, 2011·Journal of Molecular Modeling·Xiu-Long ShenQing-Zhi Gao
Mar 23, 2005·Bioorganic & Medicinal Chemistry·Gary H PosnerThomas W Kensler
May 7, 1999·Bioorganic & Medicinal Chemistry Letters·K YamamotoS Yamada
Jun 27, 2001·Bioorganic & Medicinal Chemistry·M ChoiS Yamada
Mar 4, 2000·Proceedings of the National Academy of Sciences of the United States of America·K YamamotoS Yamada
Jan 16, 2007·The Journal of Steroid Biochemistry and Molecular Biology·Pierre J De ClercqRoger Bouillon
Mar 21, 2007·The Journal of Steroid Biochemistry and Molecular Biology·Mathew T MizwickiAnthony W Norman
Apr 20, 2010·The Journal of Steroid Biochemistry and Molecular Biology·Mathew T MizwickiAnthony W Norman
Mar 30, 2010·The Journal of Steroid Biochemistry and Molecular Biology·Silvina Eduardo-CanosaAntonio Mouriño
Jul 1, 2004·The Journal of Steroid Biochemistry and Molecular Biology·Pierre J De ClercqRoger Bouillon
Sep 8, 2006·Organic Letters·Wim SchepensPierre J De Clercq
Jun 9, 2020·Journal of Medicinal Chemistry·Izabela K Sibilska-KaminskiHector F DeLuca
Oct 14, 2000·The Journal of Organic Chemistry·A Fernández-GacioA Mouriño

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