Generous funding through the US National Institutes of Health
Under the co-ordination of last year’s Nobel Laureate in Chemistry, Prof. Brian Kobilka of Stanford University, an interdisciplinary team of researchers has been formed to research pharmaceuticals. Its members include Prof. Peter Gmeiner and his research group at FAU’s Department of Chemistry and Pharmacy. In four highly specialised laboratories around the world, the scientists work on designing and developing new active agents that connect with the G protein-coupled receptors (GPCR) – a family of receptors that is responsible for the communication between nerve cells. The US National Institutes of Health are supporting the project with six million dollars over a period of five years.
GPCR constitute the largest family of molecular points of attack for pharmaceuticals: the effects of more than a third of all pharmaceuticals are the result of interactions with GPCR. Antihypertensive beta blockers, for instance, work by inhibiting the function of a GPCR from the family of adrenergenic receptors. Strong painkillers such as morphine work by activating opioid receptors, which also belong to the class of GPCR. Humans produce approximately 800 different GPCR, but only a small percentage of GPCRs has been researched so far. Together with his new research partners, last year’s Nobel Laureate in Chemistry Brian Kobilka wants to change that.
Already in 2011, close collaboration between the laboratories of Kobilka and Gmeiner resulted in the first x-ray crystal structure – a three-dimensional image that makes even individual atoms visible – of a GPCR connected to an activating agent. The newly-founded research group is planning to develop novel pharmaceuticals with higher efficacy or less side effects based on the insights that can be won using such crystal structures.
While crystallisation experiments and other structure-biological examinations are carried out in Brian Kobilka’s laboratory at Stanford, the working group of the computational chemist Brian Shoichet at the University of Toronto intends to use the new crystalline structures to digitally examine several million potential active agents with regard to their interactions with G protein-coupled receptors. The promising agents, called ‘hits’ in technical jargon, are then to be examined in highly specialised in-vitro studies at Roger Sunahara’s laboratory at the University of Michigan.
The researchers will pay special attention to those agents that interacted at the GPCR not with the binding site of a messenger substance produced in the body, such as adrenaline, but with independent binding pockets (allosteric binding sites). This kind of control of GCPR promises to allow for high accuracy in docking onto a desired GPCR and influencing physiological processes in a more ‘natural’ way.
Lastly it will be the task of Peter Gmeiner and his working group to further chemically modify and optimise the hits and to construct bespoke agents for GPCR, which, in combination with cleared receptors, could provide Kobilka’s laboratory with new crystal structures. ‘This new working group gives us the opportunity to revolutionise pharmaceutical research,’ says Prof. Peter Gmeiner.
Prof. Dr. Peter Gmeiner
Phone: +49 (0)9131 85 24116