It’s about time: Monash research adds a new dimension to drug discovery

It’s about time: Monash research adds a new dimension to drug discovery

21 March 2016

Eliminating the side effects that plague many therapeutic drugs is one of the major aims of contemporary medical research. In a new paper that has major implications for the way future drug discovery programs are designed, Monash researchers have revealed an unappreciated impact of time upon contemporary approaches used to design more selective drugs that minimise side-effects.

About a third of the drugs on the market target human proteins called G protein-coupled receptors (GPCRs), which are found all over the body and are involved in numerous diseases and disorders. When GPCRs are activated by a drug, the receptor sends an array of signals that, in turn, cause changes in cell function. But although these some of these cellular changes can be therapeutically beneficial, others result in side effects.

A particularly hot topic in the field of GPCR drug discovery is a phenomenon called "biased agonism". Biased agonism describes the ability of certain drugs to restrict GPCRs to sending off only a portion of their available signals, while leaving the other signals untouched. This gives rise to the exciting possibility of designing drugs that avoid the side effects associated with the activation of "bad" signals while keeping the therapeutic effect caused by the activation of "good" signals.

A new study from the Monash Institute of Pharmaceutical Sciences, published in the prestigious journal Nature Communications, reveals time as an important factor that has so far been largely neglected in research around biased agonism. The findings of this study, led by Dr Rob Lane and Professor Arthur Christopoulos of the Drug Discovery Biology theme at Monash Institute of Pharmaceutical Sciences, reveal that some medications can bind to their receptor for long periods of time, and that the signals they induce the GPCR to send can also change over time.

"The interplay between these two factors means that the effect of a drug can change over time. This means that biased agonism can also change with time. We even observed a complete reversal in the direction of biased agonism between different signals for some of the drugs we studied. This is important because in most studies of biased agonism (and novel drug screening in general), drug effects are measured at a single time point." says Dr Lane.

"Such single-time-point measurements give an incomplete picture of drug action. We now propose that these kinetic factors must be incorporated routinely into future drug discovery programs in both the pharmaceutical industry and in academia aiming to discover biased agonists," adds Professor Christopoulos.

In order to establish the bias profiles that would be most beneficial in producing therapeutic effects, researchers have been searching for biased agonism in existing medications. But the bias profiles that have been determined for the same medications across different studies are often inconsistent . The reason for these discrepancies was unclear – until now.

"We examined a drug called Abilify®, which is used to treat schizophrenia and for which there was a lot of inconsistent data around its bias profile," said Monash PhD student and first author of the study, Carmen Klein Herenbrink. "By looking at the action of the drug over time, we were able to account for those discrepancies."

This research is a result of ongoing collaborations with the Medicinal Chemistry theme of Monash Institute of Pharmaceutical Sciences, Columbia University in the USA and University of Nottingham in the UK.