INHIBITION OF BILIRUBIN UDP-GLUCURONOSYLTRANSFERASE - A COMPARATIVE MOLECULAR-FIELD ANALYSIS (COMFA)

Two series of compounds structurally related Co phenolphthalein and tr iphenylalkyl carboxylic acid were tested as inhibitors of bilirubin gl ucuronidation catalyzed by rat liver microsomal UDP-glucuronosyltransf erase, and analyzed by the CoMFA method in order to predict the inhibi tory potency of these structures and afford a three dimensional struct ure of the bilirubin binding site. These substances could inhibit bili rubin glucuronidation to different extents. Their inhibitory potency w as quantitated in terms of I-50 values. The best inhibitors exhibited competitive inhibition. The 3D-QSAR results led to a fairly good predi ction of the inhibitory potency of these two series of compounds. They indicate a correlation between the inhibitory activity of the glucuro nidation reaction and the steric and electrostatic fields with a relat ive contribution of 43% and 57%, respectively.