Targeting nuclear receptors with novel synthetic ligands

我的建议包括三个部分，都与药物设计的一般领域有关。第一部分改进药物与蛋白质靶标结合亲和力的计算。第二部分：创造一整套雌激素受体激动剂和拮抗剂。第三部分。创造一种改进形式的“多肽贴片”来阻断雌激素受体的激活(S)。原理：雌激素受体和激活它们的雌激素(包括女性荷尔蒙雌二醇和雌酮)对于决定女性的性特征和帮助预防诸如骨质流失、心脏病发作和中风等疾病是必不可少的。绝经后，雌激素水平下降了90%，女性容易患上这些疾病，还会出现潮热等其他症状。因此，直到最近，而且在很大程度上，许多绝经后的妇女开始了一种被称为激素替代疗法(HRT)的雌激素补充制度。然而，流行病学数据表明，长期使用HRT会增加患乳腺癌和子宫癌的风险。该提案中描述的项目旨在为HRT创造更安全的药物。它们还将有助于了解癌症，特别是乳腺癌是如何发展的，以及如何通过我们正在努力开发的新化合物来控制它们。

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.