Decoding the relationship between the molecular structure and sweetness intensity of plant-derived chalcones based on 3D-QSAR

Natural plant-derived chalcones exhibit sweetening properties and bioactive health benefits, making them promising natural sweeteners. However, their unsatisfying sweetness intensity restricts their applications in the food industry. To clarify the structure-sweetness relationship, 25 chalcones were characterized for their sweetness threshold and structural features using sensory evaluation and molecular superposition. The quantitative conformational relationship on the structure-sweetness of chalcones was explored by 3D-QSAR based on comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA). Results showed that introducing a negatively charged group at the C2 site of ring A, a positively charged group at the C4 site, and a small-volume group with a positive charge at the C6 site could effectively increased the sweetness. Additionally, a negatively charged group at the C3' site of ring B and large-volume groups at the C4' and C5' sites were helpful in improving the sweetness. The sweetness intensity of some chalcones was predicted and evaluated, and the results followed with the proposed model, confirming the validation of 3D-QSAR. Molecular docking also verified the model's findings. This study provided theoretical insights into the structure-sweetness relationship of chalcones, offering potential information for understanding the sweetness from natural plants and a foundation for the development of natural sweeteners with improved sweetness and functional benefits.