A highly selective structure-based virtual screening model of Palm I allosteric inhibitors of HCV Ns5b polymerase enzyme and its application in the discovery and optimization of new analogues.

First structure-based activity prediction model of topologically diverse inhibitors of Palm I allosteric site of HCV NS5b polymerase enzyme is reported here. The model is a workflow of structure-based pharmacophore followed by guided docking. The pharmacophore was constructed using a novel procedure which includes PLIF (protein ligand interaction fingerprint), Hypogen, contact-based pharmacophore and shape constraints. The guided docking was tweaked using both a scoring function of high correlation with activity (ChemPLP) and essential pharmacophore features. Statistically, ROC analysis for the workflow, deploying the novel technique of virtual decoys, yielded AUC of 0.947. Experimentally, the model was used to screen Asinex GOLD database yielding a new hit with a different scaffold which was further confirmed by synthesis and biological evaluation.