Discovery of novel Hepatitis C virus inhibitor targeting multiple allosteric sites of NS5B polymerase.

We present the discovery of a novel synthetic compound that harbors the potential of NS5B polymerase inhibition. All eight compounds belonging to the benzothiazine family of heterocycles displayed no cellular cytotoxicity in HepG2 cells at nontoxic dose concentration (200 μM). Subsequently, among eight compounds of the series, merely compound 5b exhibited significant inhibition of the expression of the HCV NS5B gene as compared to DMSO control in semi-quantitative PCR. Based on our western blot result, 5b at the range of 50, 100 and 200 μM induced 20, 40, and 70% inhibition of NS5B protein respectively. To estimate the binding potential, 5b was docked followed by molecular dynamics (MD) simulations in explicit solvent for a period of 20 ns. Binding free energy calculation by MM-GB/PBSA method revealed a conserved interaction profile with reported NS5B co-crystallized inhibitors and residues lining the allosteric sites. The results presented provide important information about a novel compound 5b, for the discovery of novel inhibitors that tends to target multiple sites on NS5B polymerase. PMID: 32485331 [PubMed - as supplied by publisher]
Source: Infection, Genetics and Evolution - Category: Genetics & Stem Cells Authors: Tags: Infect Genet Evol Source Type: research