A molecular modeling study of the interactions between the antiestrogen drug tamoxifen and several derivatives, and the calcium-binding protein calmodulin.
The interactions of the antiestrogenic drug tamoxifen with the calcium-binding protein calmodulin have been studied by computerized molecular modeling methods. Sites in both the N and C domains of the protein have been established, with one in the C domain having the highest calculated enthalpy of binding. The residues involved in the sites have been detailed. Modeling studies are reported for six tamoxifen derivatives, and their calculated enthalpies of binding are compared with the ability of the analogues to inhibit calmodulin-dependent cyclic AMP phosphodiesterase (PDE) (Rowlands et al. Biochem, Pharmacol. 1990, 40, 283-289). The poor binding properties of the piperazino and C-methyl derivatives are correctly predicted, whereas the superior affinity of 4-iodotamoxifen is not fully explained by the model.
Edwards
K J
KJ
Cancer Research Campaign Biomolecular Structure Unit, Institute of Cancer Research, Sutton, Surrey, U.K.
Laughton
C A
CA
Neidle
S
S
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D001665:Binding Sites; D002147:Calmodulin / Q000378:metabolism*; D003198:Computer Simulation; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D004347:Drug Interactions; D008958:Models, Molecular; D013629:Tamoxifen / Q000378:metabolism*
D002147:Calmodulin; D013629:Tamoxifen; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1