Anti-cancer Drug Design

Over the past two decades, impressive advances have occurred in the understanding of how a normal cell transforms into a tumor cell. Tamoxifen and Raloxifene, a kind of anti-cancer drugs that work on estrogene receptor (ER), can block the binding of Estradiol to ER and cause changes in shape of the receptor complex, blocking the action of estradiol and preventing breast cancer cell replication [100]. Tamoxifen is now widely used in breast cancer treatment. However, the fact that laboratory studies showed that there might be a link between tamoxifen and endometrial cancer shifted the emphasis away from tamoxifen but toward a general strategy for new drug development [56]. Raloxifene, which is currently marketed in several countries (not USA) for the prevention of osteoporosis in menopaused women, belongs to a new drug class called Selective Estrogen Receptor Modulators (SERM) that could combine ideal properties for a product designed for menopausal women [42]. While, the crystal structure of the raloxifene and ER complex structure was already determined [34], the structure of other SERM/ER complexes has not been established, nor has the relationship between the changes in three-dimensional structure of the ER/SERM complex and the function been elucidated.

To throughly understand the subtle balance between competing interactions involved in molecular recognition process [49], a detailed structural and dynamical description of biomolecular systems is essential. In this application we propose to use MD simulations to reveal the dynamical processes of drug/DNA binding, drug/ER binding, and their interactions to facilitate new drug design.