Novel computational pipeline approach leads to discovery of possible new treatments for the endocrine disorder hyperparathyroidism
Scientists recently used a new strategy to identify, screen, and test possible new drugs to treat hyperparathyroidism by targeting the parathyroid hormone type 1 receptor (PTHR) protein. Overactive PTHR signaling can result in hyperparathyroidism, an endocrine disorder in which the parathyroid gland makes too much parathyroid hormone. This hormone is vital for maintaining normal calcium and vitamin D levels and for proper bone turnover. However, excess parathyroid hormone works through its receptor, PTHR, to cause elevated calcium levels in the blood, which can lead to health problems such as bone thinning and kidney stones.
Seeking new ways to treat hyperparathyroidism, researchers devised a computational pipeline approach to identify and screen for compounds to affect PTHR’s function. Using a series of computer models and simulations, researchers predicted how various parts of the PTHR protein interact with each other. This approach identified specific sites on PTHR that were “druggable” (i.e., where a small molecule could bind and change the receptor’s shape and function). Scientists then used another set of simulations to screen a library of compounds virtually, looking for those predicted to bind well to the identified sites on PTHR. This computational strategy identified several promising compounds, and one of these compounds, Pitt12, was tested in both cells grown in the lab and in male mice. In both sets of experiments, Pitt12 inhibited the effects of parathyroid hormone, possibly by disrupting PTHR’s interactions with other signaling proteins. In mice, Pitt12 also reduced blood calcium levels, indicating that this compound might be useful in preventing the elevated calcium levels associated with hyperparathyroidism. Preliminary experiments also suggested that Pitt12’s inhibitory effects on PTHR did not seem to extend to other, similar receptors tested. Such specificity would be desirable in a therapeutic, though additional experiments will be needed to determine Pitt12’s suitability for further drug development.
In addition to identification of Pitt12, this study also provided broadly valuable information on PTHR. This data could inform work on drugs targeting this receptor for other purposes, such as treating bone and mineral disorders. The researchers’ new computational pipeline approach could also be adapted to identify small molecules targeting receptors other than PTHR, and thus could improve the drug development process for a wide variety of diseases.
Sutkeviciute I, Lee JY, White AD,…Vilardaga JP. Precise druggability of the PTH type 1 receptor. Nat Chem Biol 18: 272-280, 2021.