title: Conformation-function relationship of vitamin D: conformational analysis predicts potential side-chain structure.
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 of the EA region (L-EA). Thus, the side chains of almost all potent analogues were distributed around the EA region, and potency increased in the order A, F, EA, and L-EA.
authors.affiliation: Institute for Medical and Dental Engineering, Tokyo Medical and Dental University, 2-3-10 Surugadai Kanda, Chiyoda-ku, Tokyo 101, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Yamada
authors.forename: K
authors.initials: K
authors.lastname: Yamamoto
authors.forename: H
authors.initials: H
authors.lastname: Masuno
authors.forename: M
authors.initials: M
authors.lastname: Ohta
mesh_terms: D002117:Calcitriol / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D019277:Entropy; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014807:Vitamin D / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D014807:Vitamin D; D002117:Calcitriol