Using advanced mass spectrometry technology, scientists have developed a molecular model that may provide a new framework for improving the design of osteoporosis treatments.
“Because of our aging population, these kinds of therapeutics are in great demand,” said study leader Patrick R. Griffin from Scripps Research Institute in San Diego, California.
Using a technology known as HDX, which the Griffin lab has propelled into mainstream protein analysis, the scientists delivered the first dynamic snapshots of a prime target for osteoporosis treatments: a receptor that regulates calcium levels to maintain healthy bones.
The use of current drugs that target this receptor–called vitamin D receptor agonists–is limited because its use can result in hypercalcemia, a condition that can weaken bones and even cause kidney stones, due to too much calcium in the bloodstream.
“The idea is that if we could fingerprint how these various ligands interact with the vitamin D receptor, we could provide a kind of roadmap to help develop those that only trigger the non-hypercalcemia gene,” Griffin said.
Until now, developing more selective compounds has been hampered by the fact that no one understood the structural mechanism that makes them work.
“This study shows that it’s possible to develop a drug that can alter certain aspects of the complex to avoid problematic activation of TRPV6 –and the study points to novel ways to design potential therapeutics to treat osteoporosis safely and more effectively,” Griffin noted.
They performed a detailed comparative biophysical study on hundreds of compounds, all with distinct chemical structures.
The scientists used hydrogen-deuterium exchange (HDX) mass spectrometry, a high-precision, high-sensitivity mapping technique that has proven to be a robust method to probe protein conformational or shape changing dynamics within the context of ligand and protein/protein interactions.
HDX can show the specific regions of the protein complex that are altered on interaction with specific ligands, in this case the vitamin D receptor complex, information which can be used to infer structural changes that are the result of a specific interaction.
The research is published today in the journal Nature Communications.
-ANI
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