The bitterness behind sweetness: an integrated 3D-QSAR and molecular modeling approach elucidates the structure determinants of taste purity in natural chalcones.

The bitter and astringent properties of plant-derived chalcone compounds result in lower sweet taste purity compared to that of sugars such as sucrose, thereby limiting their applications. To elucidate the relationship between the structure of chalcones and their sweet taste purity, a 3D-QSAR model was established according to the sensory experiments that evaluated the sweetness and aftertaste of 22 chalcone compounds. Based on Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA), key sites and functional groups affecting the sweet taste purity of chalcones were identified. The model indicated that the sweet taste purity of chalcone compounds can be enhanced by introducing negative charges and hydrophilic groups at the C2 position of ring A, hydrophilic groups at positions C3 and C4 of ring A, and small-volume groups at position C6 of ring A, as well as introducing hydrophilic groups on ring B and large-volume groups at positions C4' and C5' of ring B. Furthermore, the chalcones compatible with the model were selected for sensory evaluations of the sweet taste purity. The results were consistent with model predictions, thereby validating the efficacy of the 3D-QSAR model. Molecular docking studies further corroborated the model's reliability. This study establishes a 3D-QSAR model for evaluating sweet taste purity scores, thereby enhancing the sensory profile of chalcone compounds. It provides novel design concepts for developing sweeteners with high sweet taste purity and offers the food industry access to high-performance sweetener options.