Searching for anthranilic acid-based thumb pocket 2 HCV NS5B polymerase inhibitors through a combination of molecular docking, 3D-QSAR and virtual screening

Abstract

A combination of the following computational methods: (i) molecular docking, (ii) 3-D Quantitative Structure Activity Relationship Comparative Molecular Field Analysis (3D-QSAR CoMFA), (iii) similarity search and (iv) virtual screening using PubChem database was applied to identify new anthranilic acid-based inhibitors of hepatitis C virus (HCV) replication. A number of known inhibitors were initially docked into the “Thumb Pocket 2” allosteric site of the crystal structure of the enzyme HCV RNA-dependent RNA polymerase (NS5B GT1b). Then, the CoMFA fields were generated through a receptor-based alignment of docking poses to build a validated and stable 3D-QSAR CoMFA model. The proposed model can be first utilized to get insight into the molecular features that promote bioactivity, and then within a virtual screening procedure, it can be used to estimate the activity of novel potential bioactive compounds prior to their synthesis and biological tests.

• 3D-QSAR CoMFA
• HCV replication inhibitors
• molecular docking
• PubChem database
• virtual screening

Declaration of interest

Authors report no declarations of interest.

This work is supported by funding under the Seven Research Framework Program of the European Union. Project SYSPATHO (ex. PATHOSYS – HEALTH-F5-2010-260429).