Binding Mode Prediction and Validation of Bile Acid and Neurosteroid Agonists of TGR5

TGR5 is the first bile acid sensing G-protein coupled bile acid receptor (GPCR) GPCR and directly interacts with several G-protein subtypes [1]. High expression levels of TGR5 are found in the brain, the liver, and the gastrointestinal tract. TGR5 is an emerging target for the treatment of metabolic diseases [2 – 4]. Therefore, developing selective and potent agonists of TGR5 is of high importance [5]. However, without an x-ray crystal structure or an experimentally determined binding mode, the rational design of compounds is difficult. Here, we present an experimentally validated binding mode of 68 natural and…