New research discovery could advance drug treatments for diabetes and obesity
Scientists have unlocked new details on important ‘receptor’ proteins –promising targets for the creation of novel drugs for metabolic conditions ranging from diabetes to obesity and inflammatory disorders.
The discovery – published today in Nature and led by Queen’s University Belfast, the University of Glasgow and the University of Pittsburgh – describes ‘atomic level structures’ of an important receptor protein in complex with three different activators, all of which interact and produce their effects in distinct ways.
The researchers believe the new, detailed information on these protein complexes could greatly assist in the discovery of new treatments.
The team studied a receptor, called FFA2, that is normally activated by short-chain fatty acids which are produced when gut bacteria ferment dietary fibre—compounds that promote positive health outcomes from gut to brain.
Due to it's presence in immune cells, the pancreas, fat cells, and hormone-producing cells that control insulin levels and satiety, FFA2 represents a promising drug target for metabolic disorders including diabetes and obesity.
The researchers used three different chemical classes of synthetic ‘ligands’ identified by the pharmaceutical industry to activate this receptor and found each to work on FFA2 at different places.
Dr. Irina Tikhonova from the School of Pharmacy at Queen’s University Belfast said:
"Our molecular dynamics simulations using the Kelvin-2 supercomputer at Queen’s revealed how each compound uniquely changes the receptor's shape, explaining their different signalling profiles. This computational approach was essential for connecting static structures with dynamic biological function."
Prof Graeme Milligan, Gardiner Chair of Biochemistry at the University of Glasgow’s School of Molecular Biosciences, said: “We are thrilled with our discoveries and believe this work could be extended to be applied across similar receptor proteins that are currently the molecular targets for 35% of clinically used medicines. These principles could have enormous reach and possibility in the world of drug discovery.”
The work demonstrated that each compound makes short-chain fatty acids function more effectively—but through different mechanisms—allowing for the possibility of tuning this selectivity to improve pancreatic function, enhance immune cell responses, or control fat storage in adipose tissue.
The study, ‘Allosteric modulation and biased signalling at free fatty acid receptor 2,’ is published in Nature. The study was supported by funding from the National Institutes of Health (NIH) in the USA, the Medical Research Council (U.K.), the Biotechnology and Biological Sciences Research Council (U.K.), the Lundbeck Foundation, and the EPSRC.
Media
For media enquiries please contact Grace White, Strategic Communications at Queen’s University Belfast: g.white@qub.ac.uk