Exploiting ChEMBL database to identify indole analogs as HCV replication inhibitors

• Exploiting ChEMBL database to identify novel HCV replication inhibitors.
• Virtual Screening combining KNIME workflows (Enalos KNIME nodes) and 3D-QSAR CoMSIA.
• Identifying several promising chemistry driven compounds with potential high activity.

Molecular docking, 3D-QSAR CoMSIA and similarity search were combined in a multi-step framework with the ultimate goal to identify potent indole analogs, in the ChEMBL database, as inhibitors of HCV replication. The crystal structure of HCV RNA-dependent RNA polymerase (NS5B GT1b) was utilized and 41 known inhibitors were docked into the enzyme “Palm II” active site. In a second step, the docking pose of each compound was used in a receptor-based alignment for the generation of the CoMSIA fields. A validated 3D-QSAR CoMSIA model was subsequently built to accurately estimate the activity values. The proposed framework gives insight into the structural characteristics that affect the binding and the inhibitory activity of these analogs on HCV polymerase. The obtained in silico model was used to predict the activity of novel compounds prior to their synthesis and biological testing, within a Virtual Screening framework. The ChEMBL database was mined to afford compounds containing the indole scaffold that are predicted to possess high activity and thus can be prioritized for biological screening.

Figure optionsDownload as PowerPoint slide