Computational study of effectiveness of anti breast-cancer drugs

Although crystal structure would suggest that anti-estrogens induce conformation changes, further disrupt dimerization of the ER, and eventually stop growth of breast cancer, the precise mechanism of the inhibitory effect is still unclear [97]. By using MD simulations, the details of the mechanism will be explored and further evaluate these compounds. The isolated DBD of the ER was proven to be monomeric in solution; however, two DBDs bind highly cooperatively as homodimers to the response element. The simulation of DBD in complex with ER element demonstrated that the dimer induces a bent and underwound conformation in the receptor dimer and a similar bent and underwound conformation is observed for nucleosomal DNA [10,57]. The simulations of ER$\alpha$ LBD in complex with a number of known agonist and putative xenoestrogens were carried out and revealed that interactions between raloxifene substituent and helix 12 prevent the structural rearrangement seen in the E2/ER LBD complex, thereby blocking the dimerization of ER and eventually, other estrogenic activities, which showed close agreement with experimental data [72].