Researchers Describe Mathematical Model as Key to Developing Effective Medications for Brain Disorders

Collaboration between researchers from the Institute of Neuroscience UAB (INc) and the pharmaceutical company GlaxoSmithKline, published in March Trends in pharmacological sciences, describes a mathematical model for quantifying the activity of biased G protein-coupled receptors.

G-protein coupled receptors are present in many neurological and psychological disorders through the activation of G proteins. In addition to activating G protein, they are also able to activate proteins responsible for Other signaling pathways, thus achieving more effect at a time. These effects may be beneficial or harmful, and for this reason, controlling them by directing the signal in the proper direction is a therapeutic goal. An example of this type of treatment is chronic pain and opioid medication treatment. Morphine releases its therapeutic effects by binding to the μ-opioid receptor and by activating the signaling pathway of G proteins, but also by the same receptor, it produces the undesirable effects via the β-arrestin pathway. One current line of research found in pharmaceutical companies is the design of drugs that bind to the μ-opioid receptor specifically to activate the G protein pathway.

Innovation in the design of new drugs must go hand in hand with the development of new theoretical frameworks to define reliable measures for pharmaceutical properties that need to be improved. In this study, researchers further investigated the quantification of biological signal bias by the inclusion of unbound receptor activity (constitutive activity or basal receptor activity). Thus, there is an increase in the pharmacological space available for the discovery and quantification of new agonist drugs, neutral antagonists and inverse antagonists (ligands that increase, modify or decrease the basal receptor activities).

"Given the fact that, for a specific receptor, a signaling pathway might be related to therapeutic effects, while another might have adverse effects, the quantification of a skewed signaling pathway of the receptors is fundamental for the design of more accurate drugs, producing fewer side effects, "says Dr. Jesús Giraldo, study coordinator and head of the laboratory of molecular neuropharmacology and bioinformatics of the Institute of Neuroscience of UAB (INc). Dr. Giraldo adds that "the next step will be to integrate the model into the systematic and systematic badysis of new drugs to verify its validity in real-life situations".