Computational study of effectiveness of anti breast-cancer drugs

Estrogen receptor (ER) is an important pharmaceutical target for hormone replacement in menopausal women and for chemotherapeutic drugs against certain reproductive cancers. ER, which functions as a ligand-activated transcriptional regulator, has two subtypes: ER$\alpha$ and ER$\beta$. Both of them contain N-terminal transactivation (AF-1) domain, DNA- binding domain(DBD), C-terminal ligand-binding domain (LBD) and transactivation domain (AF-2) [61]. A wide repertoire of structurally distinct compounds bind to ER with differing degrees of affinity and potency [17]. Selective ER modulators (SERMS), such as tamoxifen, raloxifene and ICI 182,780, have the ability to act as both agonists and antagonists depending on the cellular and promoter context as well as the ER isoform targeted. Since 1997, there has been an explosion of high-resolution structural data on ER LBDs. The crystal structures of human ER$\alpha$ LBD in complex with E2, tamoxifen, raloxifene, respectively, are available. Rat ER$\beta$ LBD in complex with raloxifene are also available. The crystal structure revealed that several helices (particularly helices 11 and 12) are crucial for activity [72]. These have allowed to study the changes undergone by ER upon binding of drugs, and the prediction of resulting alterations in biological function.