title: 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.
abstract: 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.
authors: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, 6 b abadeer zeitoun, Cairo 11566, Egypt. amr.hamed@pharm.asu.edu.eg
authors: Amr H
authors: AH
authors: Mahmoud
authors: Dalal A
authors: DA
authors: Abou El Ella
authors: Mohamed A H
authors: MA
authors: Ismail
authors: Khaled A M
authors: KA
authors: Abouzid
mesh_terms: D000495:Allosteric Site; D000998:Antiviral Agents / Q000737:chemistry*; D019540:Area Under Curve; D055808:Drug Discovery; D016174:Hepacivirus / Q000737:chemistry*; D057166:High-Throughput Screening Assays; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D062105:Molecular Docking Simulation; D012372:ROC Curve; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014584:User-Computer Interface; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D008024:Ligands; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase