CONFORMATION-FUNCTION RELATIONSHIP OF VITAMIN-D - CONFORMATIONAL-ANALYSIS PREDICTS POTENTIAL SIDE-CHAIN STRUCTURE

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 r eceptor (VDR) affinity of 1 alpha,25-dihydroxyvitamin D-3 derivatives increases, in terms of side-chain region, in the order EG, G, A, and E A. 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 1 alpha,25-dih ydroxyvitamin D-3 analogues. We initially listed structural modificati ons in the side chain of potent vitamin D analogues and estimated thei r potency factor. Possible side-chain conformations of representative analogues were calculated by the molecular mechanics method and plotte d on a dot map compared with the regions A, G, EA, and EG. The cell-di fferentiating 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-ox a, 22-ene, 16-ene, or a 18-nor modification were located in front of r egion 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 E A region(L-EA). Thus, the side chains of almost all potent analogues w ere distributed around the EA region, and potency increased in the ord er A, F, EA, and L-EA.