Deadenylase enzymes as potential novel drug targets in osteoporosis, bone disease, and repair

在英国，45岁以上的女性因骨质疏松症住院的时间比心脏病、糖尿病或乳腺癌多。由于骨密度降低而导致的常见髋部、手腕和脊柱骨折对NHS来说是一项巨大的经济成本，并对发病率和生活质量产生重大影响，特别是对妇女和老年人。尽管预防和治疗骨质疏松症有几种选择，但目前可用的药物并不总是有效的。此外，由于副作用，并不是所有的患者都能耐受可用药物。如果成功，我们的项目是迈向未来可能对治疗骨质疏松症、骨骼疾病和修复有用的新药的第一步。与目前的药物相比，这些未来的药物将具有更令人满意的特性。它们将以药片的形式上市，副作用较少，并通过刺激骨形成细胞直接促进骨形成。在骨形成细胞中选择酶靶标的想法来自于对骨骼肥大的基因工程小鼠的研究，并对相关酶进行了非常详细的研究。我们将使用机器人筛选数千种化合物的大集合，以寻找类药物分子。同时，我们将使用高性能计算机集群来筛选一个数据库，其中包含多达100万个化合物的信息，使用？化学信息学？然后，我们将使用合成化学来优化我们的点击，并通过观察细胞培养皿中的骨形成来测试我们化合物的活性。如果成功，我们的研究将确定可能代表未来药物开发候选的分子。

In the UK, women over 45 years old spend more time in hospital due to osteoporosis than heart disease, diabetes or breast cancer. Common hip, wrist, and spinal bone fractures due to decreased bone density are a huge financial cost to the NHS and impact significantly on morbidity and the quality of life, in particular of women and the elderly. Although several options are available for the prevention and treatment of osteoporosis, currently available drugs are not always effective. Moreover, not all patients tolerate the available medications due to side-effects. If successful, our project is the first step towards novel drugs of the future that may be useful for the treatment of osteoporosis, bone disease and repair. These future drugs will have more desirable characteristics compared to current medications. They will be available as tablets, have fewer side-effects and enhance bone formation directly by stimulating bone-forming cells. The idea behind the selection of the enzyme target in bone-forming cells comes from genetically engineered mice with heavy bones and studying the relevant enzymes in great detail. We will search for drug-like molecules by screening a large collection of thousands of compounds using robots. In parallel, we will use high-performance computer clusters to screen a database with information of up to 1 million compounds using ?cheminformatics?. We will then optimise our hits using synthetic chemistry and test the activity of our compounds by looking at bone formation in cell culture dishes. If successful, our research will identify molecules that may represent candidates for future drug development.