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In drug design, a loose fit may be best bet

Chemical knockoffs resembling a key thyroid-related hormone are, in certain cases, more effective than the real thing at activating the target receptor, says a new study conducted in part by researchers at the National Institute of Diabetes and Digestive and Kidney Diseases

(NIDDK) and the National Institute on Deafness and Other Communication Disorders (NIDCD), two of the National Institutes of Health (NIH). The improved performance is related to how closely couple the chemical and receptor are, the scientists conclude, with a loose connection being more effective than a tight one. The findings are at odds with the widely held notion that the stronger the association between a hormone and its receptor, the more effective its cellular signaling. If the findings hold true for similar hormone-receptor reactions, they could help change the way that drug therapies are designed for a host of health problems, from smell and taste disorders to heart disease, asthma, migraine, and pain. The study is published in the May 12, 2006, issue of the "Journal of Biological Chemistry".

The researchers looked at thyrotropin-releasing hormone, or TRH, a hormone released in the brain that kicks off a chain of events throughout the body, including the stimulation of the thyroid gland. As with many of the body's hormones, cells recognize TRH using a receptor belonging to a mega-family of proteins known as G-protein-coupled receptors (GPCRs), which play a lead role in cell-to-cell communication. When a hormone binds to its designated GPCR on the outside of a cell, a specific G-protein is activated within the cell, initiating a cascade of biochemical events leading to the unique and appropriate cellular response to that hormone.

"GPCRs are the targets of roughly a third of medicines sold today, so if this finding for TRH holds for other GPCR targets, it could have significant implications for drug development," says Marvin C. Gershengorn, M.D., director of NIDDK's Di
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Source:NIH/National Institute of Diabetes and Digestive and Kidney Diseases


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