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Disease and treatment

Danish researchers develop many candidates for promising antidiabetes target

For many years, researchers have known that a specific receptor is an ideal target for developing candidates for medicine to combat diabetes, but so far all efforts have failed. Now Danish researcher Thomas M. Frimurer and his group have used computer simulation to develop a series of new potential medicines to treat diabetes.

Free fatty acid receptor 1 (FFAR1) is one of the golden therapeutic targets for developing medicine to treat diabetes. Several clinical trials have shown that stimulating FFAR1 enables people with diabetes to better control the disease and to lose weight. Many pharmaceutical companies have therefore invested huge sums to become the first to discover medicine that targets FFAR1.

So far, these efforts have led to many candidates being tested in Phase 3 clinical trials, but unfortunately they have all failed. All potential medicine tested on FFAR1 has harmed the liver and has therefore been rejected in Phase 3, resulting in massive financial loss.

Now Danish researchers have approached this task differently. Using computers to simulate the dynamics of molecular systems, they have developed new potential drug candidates capable of activating FFAR1 in different ways that will hopefully not harm the liver.

“Everyone thought that many of the medicines researchers tried to develop to target FFAR1 would become blockbusters, but this has not happened. In our study, we used a new method to find new mechanisms and substances that can modulate the function of FFAR1. The interesting thing about these substances is that they are new and function differently from those previously used to target FFAR1. This may potentially revive FFAR1 as an interesting therapeutic target in treating diabetes,” explains the leader of the research group behind the new study, Thomas M. Frimurer, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.

The new study has been published in the Proceedings of the National Academy of Sciences of the United States of America.

Computer model generates antidiabetes candidates

Thomas M. Frimurer’s research aims to develop medicine through structure-based design. This uses advanced computer simulation of molecular dynamics and large databases of chemical reagents and chemical pathways to very accurately model the ideal structure of a molecule that can bind to a specific protein or receptor within the body.

For example, if the target is to stimulate or block a receptor involved in regulating type 2 diabetes or the development of cancer, Thomas M. Frimurer’s computer model can predict hundreds of potential therapeutic candidates.

The researchers can use computers to screen hundreds of millions of substances to determine whether any have a chemical structure that can bind to the receptor. They then use modelling to reduce the number to a few hundred, which chemists highly skilled in synthesis have then produced using specific synthesis routes.

The computer simulation not only determines which molecules will bind effectively to the receptor but also how to make them using synthetic chemistry.

Last but not least, the researchers tested the potential therapeutic candidates in cell experiments in the laboratory and confirmed that they actually modulate the function of FFAR1 in a new way.

Thomas M. Frimurer’s research is thus taking a decisive step from knowing the structure of a protein or receptor to developing a new method of targeting the protein or receptor.

“The good thing is that we can design synthetic molecules that bind much more effectively to the receptors or proteins than their natural counterparts. So if we know of an effect in nature that would work really well if it were amplified, we can then create this synthetically,” explains Thomas M. Frimurer.

Using the computer model to develop potential anticancer medicine

Thomas M. Frimurer’s advanced computer model also helps researchers working on developing medicine to treat people with cancer.

During strenuous physical work, the body secretes lactate into the blood. Lactate is a waste product and acts as a specific signalling chemical for the hydroxycarboxylic acid receptor 1 (HCA1), which is thus activated by lactate.

A phenotypic hallmark of cancer cells is that they have reprogrammed their metabolism to produce and use lactate as the main energy source to promote growth and metastasis formation. This also means that inhibiting the lactate receptor in cancer cells can inhibit tumour growth.

Thomas M. Frimurer’s research group is one of the first in the world to use computer models to identify synthetic drugs that can inhibit HCA1.

“We have tested these substances in cancer cell lines and confirmed that they work. We are now finding partners so we can test them in animal experiments and hopefully later in human trials,” says Thomas M. Frimurer.

Helping colleagues to develop therapeutic candidates

Thomas M. Frimurer explains that the work of his research group bridges the common gap between basic research and commercializing the relevant discoveries.

Researchers often find new proteins or receptors that may have interesting pharmaceutical value, but they rarely go beyond merely reporting the discovery of the protein or receptor.

“Our major goal is to enable us and our colleagues to commercialize basic research. When someone finds that a receptor or protein has an interesting property, we can help them by making therapeutic candidates they can test. It is quite unique that we can do this so quickly through computer simulation. Few in academia can do this,” says Thomas M. Frimurer.

Molecular dynamics–guided discovery of an ago-allosteric modulator for GPR40/FFAR1” has been published in Proceedings of the National Academy of Sciences of the United States of America. The main authors are employed at the Novo Nordisk Foundation Center for Basic Metabolic Research and the Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.

Thomas Michael Frimurer
Associate Professor
The Frimurer Group investigates how small molecules and drugs interact with target proteins to modulate their function, with special interest in translational pharmacology and rational design of next generation drugs. Identification of new biological target molecules is needed to develop new drugs to treat diabetes and obesity. Potential target proteins are often discovered as e.g. gene hits in large genetic or epigenetic studies or through single cell transcriptomic analysis. However, protein-based biochemical assays and pharmacological tool compounds (drug candidates) to validate these target proteins are needed. The core focus of the Frimurer Group is related to translational pharmacology and rational design of next generation drugs. We use structure-based design technologies to discover ligands that can be developed into pharmacological tool compounds and early drug candidates which is used to characterize the physiological role of food and metabolite sensing receptors as well as other metabolic target proteins associated with the regulation of glucose homeostasis, adipose function and are considered high value targets for the treatment of metabolic diseases. A major goal is to determine the mechanistic action of new drug candidates in the context of human disease and establish novel pharmacological paradigms that will result in the rational design of next generation drugs.