Structure-based screening for discovery of sweet compounds

Sweet taste is a cue for calorie-rich food and is innately attractive to animals, including humans. In the context of modern diets and sedentary lifestyles, attraction to sweetness presents a significant challenge to human health. It is therefore of interest to identify molecules that elicit sweet taste sensation without the caloric cost of sugars. Because the sweet taste receptor structure has not been experimentally solved yet, a possible approach to finding such molecules is virtual screening using compatibility of candidate molecules to the homology model of sugar-binding site in the receptor. Here, structural models of the extracellular Venus Fly Trap domain of the human sweet taste receptor T1R2, known to bind sugars and several other sweeteners, were constructed. The models and scoring schemes were validated by their ability to rank known sweet tasting compounds higher than properties-matched random molecules and known non-sweet molecules. The best performing models were next used in virtual screening, retrieving recently patented sweeteners and providing novel predictions. This work underlines the opportunities and challenges for structure-based discovery methods for identification of sweet taste compounds.