Abstract The World Health Organization announced a marked increase in patients with diabetes; from 108 million in 1980 to 422 million in 2014. Diabetes causes severe complications including blindness, heart attacks and lower limb amputation with an estimated 1.5 million deaths annually caused by diabetes. Therefore, there is growing interest in identifying novel drug targets and alternative therapeutics approaches. Estrogen-related receptor α (ERRα) is a nuclear hormone receptor that regulate gene expressions related to anti-inflammatory activities, oxidative phosphorylation, biogenesis and fatty acid metabolism. Large body of data suggest ERRα as a promising therapeutic target in treating metabolic disorders, such as type 2 diabetes and metabolic syndrome. The identification of ERRα selective small molecule agonists would be valuable chemical probes and pharmacological tools to further explore the role of ERRα in diabetes. However, existing ERRα agonists lack in vivo potency and selectivity that are required for their use as chemical probes. In addition, there are no X-ray crystal structures available for ERRα bound agonists, which hindered the discovery of specific ERRα agonists. Understanding the molecular basis of agonist ligand binding to ERRα is crucial for identification and optimization of novel potent and specific agonists. Initial preliminary studies using molecular dynamics simulations, revealed the presence of novel alternate binding site in ERRα. Targeting this alternate site holds premise for discovery of novel ERRα agonists. We propose two specific aims to be done in two phases: 1) Investigation of the mechanism of agonist ligand binding to ERRα orthosteric and allosteric sites using a combination of computational and experimental approaches. This step is essential to characterize low energy state structural ensembles favouring agonist binding to ERRα. 2) Implementation of computer-based drug design approaches such as structure-based virtual screening for discovery of new molecular scaffolds that bind and selectively activate ERRα. These aims will provide novel, first in class ligands that selectively activate ERRα and can be used as chemical probes for investigation of their role in diabetes in future grant proposals.