Experimental and computational studies on molecular mechanism by which Curcumin allosterically inhibits Dengue protease

Abstract

Flaviviruses including DENV and ZIKV encode a unique two-component NS2B-NS3 protease essential for maturation/infectivity, thus representing a key target for designing anti-flavivirus drugs. Here for the first time, by NMR and molecular docking, we reveal that Curcumin allosterically inhibits the Dengue protease by binding to a cavity with no overlap with the active site. Further molecular dynamics (MD) simulations decode that the binding of Curcumin leads to unfolding/displacing the characteristic {beta}-hairpin of the C-terminal NS2B and consequently disrupting the closed (active) conformation of the protease. Our study identified a cavity most likely conserved in all flaviviral NS2B-NS3 proteases, which could thus serve as a therapeutic target for discovery/design of small molecule allosteric inhibitors. Moreover, as Curcumin has been used as a food additive for thousands of years in many counties, it can be directly utilized to fight the flaviviral infections and as a promising starting for further design of potent allosteric inhibitors.