In this research, we identified Xylopine_2, Rosmaricine_14, and Rosmaricine_15 as the top three de novo derivatives exhibiting binding affinity to H1 and N1. Addition of a pyridinum residue to the native structures of xylopine and rosmaricine contributes to bond formation at key residues in both H1 (Glu83, Asp103) and N1 (Glu228, Arg292). The de novo derivatives were predicted as active by the SVM and MLR models, and contoured well to the 3D-QSAR models. The TCM de novo derivatives were able to maintain contour while forming key binding interactions in H1, thus providing indirect support for bioactivity in H1. The results of this study indicate that the TCM de novo derivatives not only can bind to, but can also exhibit biological activities in both H1 and N1.