Targeting nuclear receptors with novel synthetic ligands

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My proposal consists of three parts, all related to the general area of pharmaceutical drug design. Part I. Improving the calculation of the binding affinity of a drug to a protein target. Part II. Creating a complete set of agonists and antagonists for the estrogen receptor. Part III. Creating an improved form of "peptide patch" to block the activation of the estrogen receptor(s). Rationale: The estrogen receptors and the estrogens which activate them (including the female hormones estradiol and estrone) are essential for determining female sexual characteristics and help to prevent diseases such as bone loss, heart attack and stroke. After menopause estrogen levels drop by 90% and women become prone to these diseases as well as suffering from other symptoms such as hot flashes. Thus, until recently, and still to a significant extent, many women after menopause began a regime of estrogen supplementation known as hormone replacement therapy (HRT). However, epidemiological data have shown that long-term HRT usage leads to an increased risk of breast and uterine cancers. The projects described in this proposal are aimed at creating safer drugs for HRT. They will also help to understand how cancers develop, particularly breast cancer, and how they can be controlled with the new compounds we are trying to develop.