Computational Assessment of Inhibitory Activity of Acridone, Xanthone and Flavone Derivatives against NS2B/NS3pro of Dengue Virus Type 2

NS2B/NS3 protease complex plays an essential role in replication of dengue virus (DENV) in the host cell. NS3 protease is a trypsin-like serine protease and NS2B acts as a cofactor. The active site of NS3 protease contains a catalytic triad made up of His51, Asp75, and Ser135 at the N-terminal region and it is involved in cleavage of the poly-protein into single functional units. Hence, targeting NS3 protease is more important in development of more potent inhibitors to control the propagation of DENV. In this study, mode of binding of acridone and xanthones, the cyclic ketones are studied with reference to that of the experimentally proven flavones and chalcones. Docking results suggest that acridone and xanthone prefer to bind the new site (the tunnel like pocket) whereas the flavone based inhibitors and cardamon in prefer to bind the active site with the catalytic triad. Moreover, the results lead to postulate the synergistic activity of xanthone/acridone with flavone derivatives to control the DENV infection. Molecular dynamics simulation and binding free energy calculations confirm the stability of acridone and flavone which bind at the tunnel and catalytic sites, respectively.