Abstract
Conformational analysis of the side chain of la, 25-dihydroxyvitamin D3 [1, 25- (OH) 2D3] and its 20-epimer revealed that the spatial region occupied by the side chain of these vitamin Ds can be divided to four areas. We designed and synthesized four diastereomers at C (20) and C (22) of 22-Me-1, 25- (OH) 2D3 whose side-chain mobility is restricted in one of these four areas. We evaluated biological activities of these four compounds. These studies allowed us to propose the relationship between the spatial region of vitamin D side-chain and the activity, an active space group concept. This concept has been generally accepted as explaining the three-dimensional structure and activity relationship of almost all known vitamin D analogs. To develop this concept to the concept including vitamin D receptor (VDR) protein, we constructed three-dimensional structure of the ligand binding domain (LBD) of the VDR by the homology modeling technique and docked 1, 25- (OH) 2D3 as a ligand into the constructed VDR-LBD.
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