High Force Research’s Roy Valentine has joined forces with scientists from Durham University, Newcastle University and Helwan University on latest research paper
Regular followers of High Force Research’s work may remember that we hit the headlines over Christmas, thanks to a new research project.
The work, which is being led by a team of scientists at the University of Aberdeen in conjunction with Durham University and High Force Research, is exploring a synthetic version of retinoic acid usually created from vitamin A – a vitamin most commonly found in a number of vegetables, including carrots and sprout – which it is hoped may be used to treat neurological disorders. The synthetic design interacts with the body’s natural receptors in a more powerful way than its regular counterparts, benefitting the brain and central nervous system.
More recently, High Force Research’s Roy Valentine has joined forces with Durham University’s Professor Andrew Whiting, Dr David Chisholm, and Dr Ehmke Pohl, Newcastle University’s Dr Christopher Redfern, and Helwan University’s Dr Hesham Haffez, to publish a research paper entitled ‘The molecular basis of the interactions between synthetic retinoic acid analogues and the retinoic acid receptors’.
The study arose from the need for a deeper understanding of receptor and ligand flexibility, and conformational freedom, with a view to aid the development of more stable and effective ATRA analogues for clinical use.
The team used molecular modelling techniques to define retinoic acid receptor interactions with the natural all-trans-retinoic acid (ATRA), and two synthetic analogues. They compared their predicted biochemical activities to experimental measurements of relative ligand affinity and recruitment of coactivator proteins. The findings were then used to inform docking studies of the synthetic retinoids.
Synthetic analogue, EC23, was found to be an excellent mimic for ATRA and was observed to have a higher binding affinity, due to an increased rigidity and linear structure. This synthetic analogue was also seen to be more potent than its natural ligand counterpart, even in lower concentrations. In addition, the research concluded that the biological activity of natural and synthetic retinoids depends on the different retinoic acid receptor types, cell-type variation, and the expression of coactivators which may determine the role of different receptor types in driving particular biological responses.
It is hoped that the research will provide improved design qualities not only in new synthetic retinoids, but also more widely in the drug industry, through a deeper understanding of the molecular interactions that create strong binding with receptors.
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