The validated CoMFA and CoMSIA maps were used to assess ligand bioactivity. Contour of the de novo compounds at 20 ns MD simulation to the relative spatial positions of CoMFA and CoMSIA feature maps are shown in Figure 11 . In Xylopine_2, Rosmaricine_14 and Rosmaricine_15, the H-bond between the 2-aminopyridinium group and Glu228 matched the electropositive group feature of the CoMFA model ( Figure 11A,11C,11E ) and the H-bond donor feature in CoMSIA model ( Figure 11B,11D,11F) . The hydrophobic benzene structures of Xylopine_2 matched the steric favoring region of the CoMFA map and the hydrophobic feature of the CoMSIA map. The carbonyl groups in Rosmaricine_14 and Rosmaricine_15 which formed H-bonds with Tyr402 satisfied the H-bond acceptor feature in the CoMSIA model. TamifluH also contours to both CoMFA and CoMSIA models. The 3-methoxypentane group close to Arg293 and Asn344 matched the steric favoring region of CoMFA ( Figure 11G ) and the hydrophobic feature of CoMSIA ( Figure 11H ). This residue has similar characteristics to the 2aminopyridinium group in the de novo derivatives. In addition, the N-methylacetamide group in TamifluH, which forms H-bond with Tyr402, is located near the H-bond donor feature in CoMSIA. Though all compounds contoured to the N1 inhibitor features identified by CoMFA and CoMSIA, a critical difference was observed between TamifluH and the TCM de novo derivatives. All compounds except TamifluH formed H-bonds at Glu228. As Glu228 is a primary binding site of N1 [99] , ability of the TCM de novo derivatives to maintain stable binding with Glu228 during MD simulation supports the potential of these compounds as drug alternatives to TamifluH.