Combined 3D-QSAR, molecular docking and molecular dynamics study on the benzimidazole inhibitors targeting HCV NS5B polymerase

摘要

The hepatitis C virus (HCV)-infected population has continued to grow during recent years, and novel HCV antiviral agents are urgently needed. In this work, a combined theoretical study was performed on the HCV non-structural 5B (NS5B) polymerase and 53 benzimidazole inhibitors. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were carried out with ligand-based and receptor-based alignments. Ligand-based QSAR models (cross-validated q(2) of 0.918 for CoMFA and 0.825 for CoMSIA) were found to be superior to receptor-based approaches (cross-validated q(2) of 0.765 for CoMFA and 0.740 for CoMSIA). Based on the most predictive CoMFA and CoMSIA models, the structural features that were essential for the inhibitory activity of benzimidazoles were characterized. A molecular dynamics study revealed that the induced fit effect between NS5B and its substrate may be responsible for the inferiority of the receptor-based CoMFA and CoMSIA models. The binding-free energy calculated using the MM/PBSA method correlated well with the experimental results and revealed that the van der Waals and electrostatic interactions most contributed to the binding. In addition, energetically favorable NS5B residues were identified by the per-residue decomposition of binding-free energy. The results presented in this work provide meaningful information for the design of novel benzimidazole inhibitors targeting the NS5B polymerase.