“…S4 pocket is aromatic box which lined by aromatic side chains of Tyr99, Phe174 and Trp215. Present research has proved that when a p4 motif embodies a cation atom, commonly nitrogen atom under protonation state, can form an arene-cation interaction to improve binding affinity, [26,27] thus the p4 motif interacted with any aromatic side chain of Tyr99, Phe174 and Trp215 can improve binding affinity resulted in the increase of Ki value. Therefore, it made the p4 motif to be various, which explained the reason why there is no pharmacophore generated in the p4 motif.…”