Identification of novel inhibitors of dengue viral NS5 RNA-dependent RNA polymerase through molecular docking, biological activity evaluation and molecular dynamics simulations

The DENV-NS5 RNA-dependent RNA polymerase (RdRp) is essential for viral replication, and one of the targets of anti-virus. In this study, the Uni-VSW module was used to virtual screen 1.6 million compounds in the ChemDiv and TargetMol (USA) database, 27 candidates were obtained. Thereby 23 candidates were selected based on their binding free energies by 50 ns MD simulations. The biological activity of the candidates and the reference compounds (BCX4430 and Compound 27) were evaluated on their IC(50) values against DENV-NGC, CC(50) values, and selectivity index. Among these, the IC(50) values of D1 and D8 were 13.06 ± 1.17 μM and 14.79 ± 7.76 μM, respectively, which were better than that of Compound 27 (IC(50) =19.67 ± 1.12 μM). The comprehensive MD simulations were performed on the candidates to assess the stability behaviour and binding mechanisms. The density functional theory (DFT) analysis was also conducted to explore the structural and electronic properties.