Multiple virtual screening approaches for finding new Hepatitis c virus RNA-dependent RNA polymerase inhibitors: Structure-based screens and molecular dynamics for the pursue of new poly pharmacological inhibitors

Multiple virtual screening approaches for finding new Hepatitis c virus RNA-dependent RNA polymerase inhibitors: Structure-based screens and molecular dynamics for the pursue of new poly pharmacological inhibitors

Blog Article

Abstract The RNA polymerase NS5B of Hepatitis C virus (HCV) is a well-characterised drug target with an active site and four allosteric binding sites.This work presents a workflow for virtual screening and its application to Drug Bank screening targeting the Hepatitis C Virus (HCV) RNA polymerase non-nucleoside binding sites.Potential polypharmacological drugs are sought with predicted active inhibition on viral replication, and with proven positive pharmaco-clinical profiles.

The approach adopted was receptor-based.Docking screens, guided with contact pharmacophores and neural-network activity prediction models on all allosteric binding sites and MD simulations, constituted Leather Toiletry Bag our analysis workflow for identification of potential hits.Steps included: 1) using a two-phase docking screen with Surflex and Glide Xp.

2) Ranking based on scores, and important H interactions.3) a machine-learning target-trained artificial neural network PIC prediction model used for ranking.This provided a better correlation of IC50 values of the training sets for each site with different docking scores and sub-scores.

4) interaction pharmacophores-through retrospective analysis of protein-inhibitor complex X-ray structures for the interaction pharmacophore (common interaction modes) of inhibitors for the five non-nucleoside binding sites were constructed.These were used for filtering the hits according to the critical binding feature of FENUGREEK - BLESSED THISTLE formerly reported inhibitors.This filtration process resulted in identification of potential new inhibitors as well as formerly reported ones for the thumb II and Palm I sites (HCV-81) NS5B binding sites.

Eventually molecular dynamics simulations were carried out, confirming the binding hypothesis and resulting in 4 hits.