Web-based information system accelerates data-driven receptor research

Breaking new ground 18. jan 2021 3 min Professor David E. Gloriam Written by Kristian Sjøgren

Every month, more than 4,000 researchers use a database on G protein–coupled receptors to design pharmacological or structural biological experiments. The updated database is now even more useful, and researchers hope that this can help to facilitate future revolutions within drug development.

One third of the world’s drugs target a specific group of proteins called G protein–coupled receptors (GPCRs).

These include antihistamines, opioids and serotonin, all of which interact with GPCRs, but cannabis and LSD must also interact with these receptors to have an effect.

Researchers developing new drugs therefore often have to design candidates that target GPCRs.

To enable this, researchers often explore large databases containing information on GPCRs to test theories, develop experimental designs and find out what other researchers are doing.

One of the world’s largest databases of this type is the GPCR database (GPCRdb).

GPCRdb has become an indispensable resource for researchers throughout the field, and it has become even more comprehensive and easier for performing experimental design.

“The purpose of GPCRdb is to make all the data available that is constantly being created by researchers worldwide, so that all interested parties can explore it when they have to design experiments or develop new drugs. The data are normally stored on the various researchers’ own computers, but here we have collected it and developed tools to analyse the data and design experiments before researchers move to the laboratory. Previously, data were in a format that was only available to data scientists and other computer specialists, but we have now also made them easily accessible to experimentalists, such as pharmacologists and structural biologists,” explains David Gloriam, Professor, Department of Drug Design and Pharmacology, University of Copenhagen.

The redesigned database has just been published in Nucleic Acids Research.

Most comprehensive database

GPCRdb contains information on the genetic sequence, structure and function of 400 human GPCRs, 43,000 protein sequences and hundreds of G proteins and arrestins (intracellular signalling molecules activated by the GPCRs).

GPCRdb contains data on 2,000 approved and experimental drugs and 200,000 other substances that can bind to and affect the GPCRs. It is constantly updated with 3D protein structures and published data on GPCRs and is the most comprehensive of its kind, which is necessary to keep up with the demand for data.

“There has been a revolution in GPCR structure determination, and this has created an abundance of data in the field. Knowledge of the structure enables researchers to determine at the molecular level how, for example, a drug will interact with a receptor. Once we know this, we can also modify the design of the drug and see whether we can make the bond stronger and the drug more effective or safer. All this can be done in GPCRdb before proceeding to the experimental work in the laboratory,” says David Gloriam.

Leading the way for researchers

David Gloriam is especially proud that the redesigned version of GPCRdb has the ability to identify the binding sites on the receptors, one of the tools that researchers use most often.

This tool enables users to visualize the three-dimensional structure of any receptor and then predict how the drugs bind to this receptor.

This could be the bond between a drug candidate and the receptor, and then researchers can see what would happen if they change either an amino acid in the structure of the receptor or an amino acid or functional/chemical group in the drug candidate.

Increasing the binding strength can make a drug more effective, but it can also make it more selective, reducing side-effects.

“A new paradigm focuses on getting drugs to not just bind to one receptor but also to activate only one cellular signalling pathway, thereby avoiding side-effects that may be associated with activating other signalling pathways. We have included how the binding between the receptor and the ligand affects signalling pathways in GPCRdb, so you know which signalling pathways you will affect and which ones you will not affect,” explains David Gloriam.

David Gloriam elaborates that these areas are the field’s most interesting ones, and they will have enormous potential in developing safer drugs.

“With GPCRdb, we have a dream of being a hub for progress and breakthroughs in this field,” says David Gloriam.

Database design tailored to researchers’ needs

David Gloriam says that receptor biology has always had research bottlenecks.

The previous bottleneck was that researchers could not generate experimental data fast enough for the other researchers who were interested in accessing them.

Today’s bottleneck is different, because now the problem is to make all the types of data available in an organized and functional way. Analytical tools that facilitate understanding of the data are also lacking.

This is exactly what the redesigned GPCRdb can do.

“In developing GPCRdb, we asked the researchers what they needed to make it as useful as possible. We used their answers to redesign the database and thus enable it to optimally support research. In fact, a section of GPCRdb has all the scientific publications in which the database has been used, including articles in very prominent journals, in which the GPCRdb was used to obtain biological insight that would have been impossible without it,” says David Gloriam.

David Gloriam says that his major goal is to get GPCRdb to catalyse even more world-class research.

“My ambition is to facilitate scientific collaboration, because scientists solve major global challenges by collaborating,” he concludes.

GPCRdb in 2021: integrating GPCR sequence, structure and function” has been published in Nucleic Acids Research. In 2018, the Novo Nordisk Foundation awarded a Hallas-Møller Ascending Investigator grant to David Gloriam for the project GPCR Biased Signalling: Illuminating the Pathways to Function and Disease. Image by Alexander S. Hauser (PhD thesis cover image).

David Gloriam started his research career at Uppsala University where he in 2006 received a PhD degree for the bioinformatic discovery of 24 human rec...

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