How Potential Diabetes Drugs Interact With Their Target

Not much is known about how synthetic compounds interact with liver receptor homolog-1 and switch it into the active state.

LRH-1 (liver receptor homolog-1) is a nuclear receptor, a type of protein that turns on genes in response to small molecules like hormones or vitamins. LRH-1 acts in the liver to regulate metabolism of fat and sugar.

Biochemist Eric Ortlund and colleagues have obtained analogous results in their study of how potential diabetes drugs interact with their target, the protein LRH-1. Their research, published in Journal of Biological Chemistry, shows that making small changes to LRH-1-targeted compounds makes a big difference in how they fit into the protein's binding pocket.

Scientists Develop Test Providing New Pathway for Identifying Obesity, Diabetes Drugs
A new molecular test that will allow researchers to look for potential drugs targeting a human metabolic enzyme believed to play a role in diabetes has been developed

‘Using X-ray crystallography, researchers have explored in detail how the liver receptor homolog-1 (LRH-1) protein interacts with two closely related LRH-1 activators.’

This research was selected as "Paper of the Week" by JBC and is featured on the cover of the December 2, 2016, issue.

Previous research has shown that activating LRH-1 decreases liver fat and improves insulin sensitivity in mice. Because of this, many research teams have been trying to design synthetic compounds that activate this protein, which could have potential to treat diabetes and nonalcoholic fatty liver disease. This has been a difficult task, because not much is known about how synthetic compounds interact with LRH-1 and switch it into the active state.

Ortlund lab researchers used X-ray crystallography to explore in detail how the LRH-1 protein interacts with two closely related LRH-1 activators, previously identified by collaborators at the University of Southampton, UK.

'Fasting Pathway' Could Pave Way For New Class Of Diabetes Drugs
Researchers at the Salk Institute for Biological Studies have discovered a novel mechanism that turns up glucose production in the liver when blood sugar levels drop - a discovery

The first author of the paper is Suzanne Mays, a graduate student in Emory's Molecular and Systems Pharmacology program. Ortlund is associate professor of biochemistry at Emory University School of Medicine. Nathan Jui, from Emory's Department of Chemistry and scientists at Scripps Research Institute in Florida also contributed to the paper.

"We were surprised to find two synthetic activators that are structurally very similar to each other interacting with LRH-1 completely differently," Mays says. "They can rotate nearly 180 degrees relative to each other in the binding pocket. This may explain why small changes to this class of molecule had unpredictable effects in previous studies."

Safety of New Diabetes Drugs Under the Scanner
Available evidence suggesting potential harm from the drugs in industry studies has not been published, an investigation by the BMJ and Channel 4 Dispatches has found.

The authors discovered a new interaction made by one of the compounds that has potential to serve as an "anchor point" to keep the compound in place. This will help researchers make compounds that better fit in the "lock" without worrying about them rotating around unpredictably. In collaboration with Jui's lab, the Ortlund lab is continuing to fine-tune the design of LRH-1 activators.

Source-Eurekalert

Regular Diabetes Drugs Linked to More Risk Of Death
As opposed to another popular drug, three broadly used diabetes medications are linked to a higher risk of death, discovers a large new analysis.