In two papers published recently in Nature, researchers from the Monash Institute of Pharmaceutical Sciences (MIPS) were part of an international team who investigated alternative drug recognition sites on G protein-coupled receptors (GPCRs) - the largest and most important family of receptor proteins in the human body.
GPCRs play a role in virtually every biological process and most diseases, including neuropsychiatric disorders, cardiovascular disease, obesity and diabetes, inflammation and cancer. Almost half of all current medications available use GPCRs to achieve their therapeutic effect.
The new research into how GPCRs work at the molecular level has unlocked vital insights into how drugs interact with this therapeutically relevant receptor family.
Professor Arthur Christopoulos from MIPS said it was hoped the research would lead to the creation of drugs that are more targeted, and with fewer side effects.
"These two studies have cracked the secret of how a new class of drug molecule, which we have been studying for some time, actually binds to a GPCR and changes the protein's structure to achieve its unique molecular effect," Professor Christopoulos said.
"This research can explain the behaviour of such drugs at the molecular level and facilitate structure-based design for new and more potent drugs."
In the first study, the labs of Professors Arthur Christopoulos and Patrick Sexton, who lead the Drug Discovery Biology (DDB) program at MIPS, Professor Jonathan Baell, from the Medicinal Chemistry program at MIPS, and their collaborators from D. E. Shaw Research and Columbia University, New York, started with a known crystal structure of a GPCR as a template, and used computer simulations to map how different drugs and the receptor can find each other, and how they change their shape and orientation as they interact. Importantly, the predictions made by the computer simulations were validated by new biological experiments and by the rational design of a more potent molecule that targets the GPCR.
In the second study, Professors Christopoulos and Sexton collaborated with US-based physician and Nobel Prize winner, Monash University Adjunct Professor Brian Kobilka, and an international team of collaborators to solve a new crystal structure (pictured) of a GPCR bound to both an activating molecule and a drug that modulates the strength of the activating molecule's signal - akin to how a 'dimmer switch' modulates the intensity of a light bulb.
This new crystal structure provides the first 'molecular snapshot' of a how a GPCR can bind two different types of drug-like molecules at the same time, and can lead to more selective 'modulator' medicines that can correct malfunctioning GPCR activity in disease.