Quantum molecular modeling of hepatitis C virus inhibition through non-structural protein 5B polymerase receptor binding of C5-arylidene rhodanines.

We have carried out high-level quantum chemical computations followed by molecular docking studies on a set of 17C5-arylidene rhodanine isomers to provide insights into the binding modes with different reported binding pockets of the nonstructural protein 5B (NS5B) polymerase that contribute to the hepatitis C virus (HCV) inhibition. We optimized the multi-target profile of the selected rhodanine analogs to investigate potential non-nucleotide inhibitors (NNIs) by quantum chemical optimization of the 18 isomers followed by docking with quantum chemically optimized structures of each isomer with NS5B polymerase at multiple binding pockets. The binding affinities of the PP-I, PP-II and TP-II pockets of NS5B polymerase were analyzed for all the 17 isomers of 2-[(5Z)-5-(2,4-dichlorobenzylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]-3-phenylpropanoic acid. On the basis of binding propensity at the different pockets and inhibitor constants, we ranked these isomers as potential candidates for the HCV inhibition. We have identified four isomers as promising NNIs of NS5B polymerase with comparable binding and inhibition to the standard (1,3) dichloro substituted isomer that exhibits in vitro activity and several other isomers as candidates in a "multi-targeted drug" approach.