Abstract: Objective: To reveal the interaction mechanism between mogroside monomers and human taste receptors at molecular level. Methods: The homologous models of sweet taste receptors (hT1R2, hT1R3) and bitter taste receptors (hT2R4, hT2R14) were established by I-TASSER Server. Model quality was evaluated according to ERRAT value, ramachandran plot, C-score and the model with the highest quality was selected. Molecular docking with Mogroside Ⅲ, Mogroside Ⅳ, Mogroside V and Siamenoside I were performed by AutoDock Vina simulation software. The sweet/bitter taste prediction model of mogroside was constructed and the sweet/bitter taste of mogroside with unknown sweetness were predicted. On the basis of this, the electronic tongue system intelligence was used to analyze the sweet/bitter characteristic values of different structures of mogroside monomers and to explore the relationship between different structures of mogroside monomers and the key attributes of sweet/bitter taste. Results: The analysis of receptor-ligand interaction showed that increasing the number of glucose groups at R1 position could reduce the bitterness of mogroside, and increasing the number of glucose groups at R2 position could enhance the sweetness and weaken the bitterness. The binding site space of sweet taste receptors was large, which was conducive to the entry of mogroside, while the binding site space of bitter taste receptors was small, which limited the entry of ligands. The sweet/bitter characteristic values measured by the electronic tongue were in high agreement with the binding free energy obtained by molecular docking, which verified the accuracy and reliability of the predicted results. In addition, the study also revealed the importance of sweet/bitter ratios in the development of taste-specific sweeteners and successfully predicted the sweet/bitter taste of mogroside sweeteners of unknown flavor. Conclusion: The sweetness of mogroside had a certain correlation with the number of glucose groups. The research results not only provide important theoretical support for the research and development of natural sweeteners, but also provide scientific basis and theoretical support for the screening and development of new natural sweeteners.