Inhibition of SARS-CoV 3CL protease by flavonoids

Jo, Seri; Kim, Suwon; Shin, Dong Hae; Kim, Mi-Sun

To elucidate the relationship between binding mode and binding affinity, a docking study for herbacetin homologues, kaempferol and morin, were also performed. The glide scores of three compounds were -9.263, -8.526 and -8.930, respectively. The tendency of the glide scores is matched with the binding affinity of the compounds. The comparison of the predicted binding modes of three complex structures showed critical factors governing their binding affinity. In common, they share the kaempferol motif. As shown in Figure 4 , the phenyl moiety of kaempferol occupies the S1 site of SARS-CoV through a hydrogen bond with Glu166. In contrast, the chromen-4-one scaffold of kaempferol locates in the S2 site. In herbacetin, total of four hydrogen bonds are formed 5 .011. S1 represents the polar S1 site of SARS-CoV 3CLpro, S2 for the hydrophobic S2 site, and the S3 0 site with no strong tendency. The pink arrows represent hydrogen bond interaction. within a distance of 2.33 Ã… in the S2 site. Especially, the major binding force was driven by the presence of the additional 8hydroxyl group which plays a critical role in binding with Glu166 and Gln189. These bindings are predicted to confer a good glide score of herbacetin. In contrast, the binding modes of morin and kaemperol become different due to the absence of above two hydrogen bonds due the lack of the 8-hydroxyl group (Figure 4) . The absence also induces the change nullifying the hydrogen bond formed by the 5-hydroxyl group of the chromen-4-one scaffold with Asp187 observed in herbacetin. Though there is a new hydrogen bond formed through the 3-hydroxyl group, it may not enough to overcome the loss of binding capacity induced by the 8-hydroxyl group. This survey shows the importance of the 8hydroxyl group at the strong binding affinity of herbacetin.