introduction
Extracellular Ca2+ plays a crucial regulatory role in many physiological processes, and the calcium sensing receptor (CaSR) is a G protein-coupled receptor (GPCR) that regulates the secretion of parathyroid hormone (PTH) and the absorption and excretion of Ca2+ by sensing changes in extracellular Ca2+ levels, thereby maintaining calcium homeostasis in vivo. The aberrant activity of CaSR has been found to be associated with a variety of diseases, including hyperparathyroidism, chronic kidney disease, osteoporosis, and certain cancers.
In patients with chronic kidney disease (CKD), renal function gradually declines, and an imbalance in calcium and phosphorus metabolism can lead to secondary hyperparathyroidism (sHPT), which leads to excessive PTH secretion, leading to bone disease, cardiovascular disease, and other complications. The regulatory role of CaSR in CKD is crucial, and when CaSR senses low calcium levels, it stimulates more PTH secretion, further exacerbating the imbalance of calcium and phosphorus metabolism, and forming a vicious circle. To stop this cycle, patients often need medications to lower PTH levels. Traditional positive allosteric modulators (PAMs), such as cinacalcet, have been approved for the treatment of sHPT in patients with CKD on dialysis. However, the side effects of these drugs, especially hypocalcemia, limit their widespread use in clinical practice.
Therefore, the development of new drugs for CaSR, especially novel PAMs that can reduce PTH levels without causing hypocalcemia, has become an important research direction for the treatment of CKD-related hyperparathyroidism. These new PAMs are expected to provide a safer and more effective treatment option for patients with CKD, reduce drug side effects and improve quality of life.
最近，美国斯坦福大学Georgios Skiniotis研究组与加州大学旧金山分校的Brian Shoichet研究组和Wenhan Chang研究组合作，在Science杂志上发表了一篇题为Large library docking identifies positive allosteric modulators of the calcium-sensing receptor（第一作者：刘芳语、吴正国）的研究论文。 该研究利用基于结构的虚拟库对接方法，筛选出了超过20种新的CaSR PAMs。
Through cryo-EM analysis, the researchers found that novel PAMs can stabilize CaSR in a new structural state, and demonstrated in mouse experiments that these PAMs can effectively reduce PTH secretion without causing hypocalcemia.
This is the first time that the effectiveness of a very large molecular library (1.2 billion molecules) has been experimentally compared with that of a conventional molecular library (2.7 million molecules). Experiments have shown that when PAMs are discovered, not only are there more abundant molecules, but these PAMs are more active. The results of the study showed that the hit rate of the new PAMs of the very large molecule library was 2.7 times higher than that of the traditional library, and the potency of the active molecule was even up to 37 times higher than that of the traditional library.
（Credit: Science）
However, the specific mechanism by which novel CaSR PAMs can reduce PTH secretion without causing hypocalcemia remains to be further studied. Future research may provide more insight into this mechanism and lead to the development of safer and more effective therapeutics.
bibliography
https://doi.org/10.1126/science.ado1868
Editor-in-charge|Explore Jun
Typography |
Article Source | BioArt”
End