Abstract
The breast anticancer drug tamoxifen and its metabolites bind serum albumins. We located the binding sites of tamoxifen, 4-hydroxytamoxifen and endoxifen on bovine serum albumin (BSA). FTIR, CD and fluorescence spectroscopic methods as well as molecular modeling were used to characterize the drug binding mode, binding constant and the effect of drug binding on BSA stability and conformation. Structural analysis showed that tamoxifen and its metabolites bind BSA via hydrophobic and hydrophilic interactions with overall binding constants of K tam–BSA = 1.96 (±0.2) × 10 4 M −1, K 4-hydroxytam–BSA = 1.80 (±0.4) × 10 4 M −1 and K endox–BSA = 8.01 (±0.8) × 10 3 M −1. The number of bound drug molecules per protein is 1.7 (tamoxifen), 1.4 (4-hydroxitamoxifen) and 1.13 (endoxifen). The participation of several amino acid residues in drug–protein complexes is stabilized by extended hydrogen bonding network with the free binding energy of −13.47 (tamoxifen), −13.79 (4-hydroxtamoxifen) and −12.72 kcal/mol (endoxifen). The order of binding is 4-hydroxy-tamoxen > tamoxifen > endoxifen. BSA conformation was altered by a major reduction of α-helix from 63% (free BSA) to 41% with tamoxifen, to 39% with 4-hydroxytamoxifen, and to 47% with endoxifen. In addition, an increase in turn and random coil structures was found, suggesting partial protein unfolding. These results suggest that serum albumins might act as carrier proteins for tamoxifen and its metabolites in delivering them to target tissues.
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