Molecular dynamic simulations may contribute to structure-based drug design

A majority of the pharmaceuticals operate by targeting the so-called “G-protein-coupled receptors” (GPCRs). In a new study, Uppsala University scientists have reported that they have developed a new way to predict how unique molecules—that can be employed in novel immunotherapy against cancer—adhere to these GPCRs.

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Described in the Angewandte Chemie journal, the calculation methods developed by the scientists represent a crucial contribution to upcoming structure-based drug design.

GPCRs belong to the protein target groups that hold a greater significance in the development of drugs. For instance, these receptors react to smells, flavors, light, dopamine, histamine, adrenaline, and an extended list of other molecules by conveying more biochemical signals within the cells. The scientists, who conducted the GPCR survey, received the Nobel Prize in Chemistry in the year 2012.

Currently, around 30% of all commercially available drugs contain GPCRs as their target proteins. A few drug molecules, like morphine, trigger the receptors (agonists), whereas others, like beta-blockers, deactivate them (antagonists).

Adenosine A2A receptor is a crucial GPCR. The antagonists of this receptor can be employed in novel immunotherapy against cancer. In collaboration with the biopharmaceutical firm Sosei-Heptares, the scientists Willem Jespers, Johan Åqvist, and Hugo Gutierrez-de-Terán from Uppsala University have successfully demonstrated how a range of A2A antagonists adhere to the receptor and deactivate it.

Thanks to molecular dynamic simulations and estimation of binding energies, the scientists were able to predict how the molecules from the pharmaceutical firm would adhere to the receptors and how robustly they do so.

As such, novel antagonists were developed and produced by chemists from Santiago de Compostela University based in Spain. X-ray crystallography was then used to determine the receptor as well as the three-dimensional structures (3D) of the complexes that form between these molecules at the experimental level.

Computer calculations were able to predict the structure as well as the binding strength in the complexes with excellent accuracy.

This is a solid step forward, and we managed to predict with great precision how this family of molecules bind the A2A receptor. Our calculation methods are now having a major breakthrough in structure-based drug design.”

Hugo Gutierrez-de-Terán, Study Lead Author, Uppsala University