A generalised fit more beneficial to drug design
recommends that a loose fit may be the best fit especially when
producing drugs for thyroid related conditions.
The findings go against the notion that the stronger the association between a hormone and its receptor, the more effective the cellular signalling. If the findings hold true for similar hormone-receptor reactions, they could help change the way that drug therapies are designed for smell and taste disorders to heart disease, asthma, migraine, and pain.
Scientists have discovered that the improved performance is related to how closely coupled the chemical and receptor are with a loose connection being more effective than a tight one.
They started by inspecting the thyrotropin-releasing hormone (TRH), which is released in the brain that stimulates thyroid gland activity.
Cells recognise TRH using a receptor belonging to a 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 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," said Marvin Gershengorn, director of NIDDK's Division of Intramural Research and senior author of the paper.
By tweaking portions of the TRH molecule, the researchers developed six slightly edited versions, while retaining most of the properties of the natural hormone.
Measuring the cellular response when hormone meets receptor, they found that the lower the affinity between the two, the stronger the signal that is elicited, with certain analogs performing up to twice as effectively as TRH.
As to why this would be the case, the researchers suggest that a loose connection between hormone and GPCR may allow a hormone to repetitively dock to and undock from its associated GPCR, activating a succession of G-proteins, and firing signal after signal.
A tight connection, alternatively, may tie up a hormone with its GPCR, activating one G-protein, and limiting its signalling ability.
"At first glance, a cellular process that affects the thyroid gland may not seem especially meaningful to the study of communication disorders," says John Northup, who heads the Section on Signal Transduction of NIDCD's Laboratory of Cellular Biology.
"However this research provides information that is fundamental to cellular signalling, a function that is essential to all cells in all systems in the body, including our sensory systems of hearing, balance, taste, and smell."
In future studies, the scientists hope to determine whether their findings are consistent with other hormone-GPCR reactions.
To illustrate just how important GPCR-based drugs are, 12 of the top 20 selling drugs, including Coreg for congestive heart failure, Cozaar for high blood pressure, Zoladex for breast cancer, Buspar for anxiety and Clozaril for schizophrenia, as well as by Zantac and Claritin, use this mechanism of action. Together the drug class accounts for $200bn (€159 bn) in annual sales.
The study is published in the May 12, 2006, issue of the >Journal of Biological Chemistry.
