Three-dimensional structure-activity relationship of vitamin D based on computational and synthetic chemistries

Conformational analysis of the side chain of 1 alpha ,25-dihydroxyvitamin D -3 [1,25-(OH)(2)D-3] and its 20-epimer revealed that the spatial region occ upied by the side chain of these vitamin Ds can be divided to four areas. W e designed and synthesized four diastereomers at C(20) and C(22) of 22-Me-1 , 25-(OH)(2)D-3 whose side-chain mobility is restricted in one of these fou r areas. We evaluated biological activities of these four compounds. These studies allowed us to propose the relationship between the spatial region o f vitamin D side-chain and the activity, an active space group concept. Thi s concept has been generally accepted as explaining the three-dimensional s tructure and activity relationship of almost all known vitamin D analogs. T o develop this concept to the concept including vitamin D receptor (VDR) pr otein, we constructed three-dimensional structure of the ligand binding dom ain (LBD) of the VDR by the homology modeling technique and docked 1,25-(OH )(2)D-3 as a ligand into the constructed VDR-LBD.