Receptors constitute attractive candidates for drug discovery since they receive signals from the environment and are implicated in disease. Diabetes and obesity remain a serious global problem, necessitating the development of novel interventions or preventative treatments. The scope of the EU-funded DDIPI (Drug discovery in interacting proteins) project was to identify compounds that bind to disease-associated receptors and inhibit their activity. Partners worked to discover novel anti-diabetic drugs that reduce serum retinol binding protein (RBP) levels, one of the hallmarks of insulin resistance and type 2 diabetes. Researchers validated one of the candidate compounds in diabetic mice through restoration of normal glucose levels and insulin tolerance. Interestingly, this drug stimulated glucose uptake via the glucose transporter independently of insulin, offering an exciting alternative to insulin treatment. Additionally, the DDIPI consortium worked on compounds targeting the G protein coupled receptors (GPCRs) linked to diabetes. Mice lacking one of the implicated GPCRs showed improved glucose tolerance and insulin sensitivity even on a high-fat diet. Scientists then tested a number of agents that selectively influence the activity of these receptors and identified several putative agonist and antagonist compounds. Considerable effort went into drugs that target the melanocortin receptor MC4R, an important component of energy homeostasis. Mutant MC4R causes insatiable appetite, leading to gross obesity and type 2 diabetes. In this context, scientists performed structural modelling and in silico screening to identify potential pharmacological chaperones capable of correcting the presumed protein misfold. Finally, the project advanced a yeast-based biosensor system to the development stage for the identification of proteins that interact with the RBP receptor. Interesting candidate proteins were identified that seem to be implicated in various disorders. Overall, the DDIPI deliverables are anticipated to advance drug discovery and accelerate the streamlining of drug hits down the drug research and development pipeline.
Drug design, receptor, diabetes, obesity, retinol binding protein, GPCR, melanocortin