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

• Published in: European journal of medicinal chemistry 2012-11, Vol.57, p.468-482
• Main Authors: Mahmoud, Amr H., Abou El Ella, Dalal A., Ismail, Mohamed A.H., Abouzid, Khaled A.M.
• Format: Article
• Language: English
• Subjects: Allosteric Site; Antiviral Agents - chemistry; Area Under Curve; Biological and medical sciences; Drug Discovery; GOLD; Guided docking; HCV; Hepacivirus - chemistry; High-Throughput Screening Assays; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Hypogen; Knime; Ligands; Medical sciences; Miscellaneous; Molecular Docking Simulation; Muse; Pharmacology. Drug treatments; PLIF; ROC Curve; Static Electricity; Structure-Activity Relationship; Thermodynamics; User-Computer Interface; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - chemistry; Virtual decoys; Virtual screening
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2012.04.016

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. A novel highly selective structure-based activity prediction model was constructed for Palm I allosteric site of HCV NS5b polymerase enzyme and applied for virtual screening. [Display omitted] ► Studies of Palm I topologically diverse inhibitors of HCV NS5b polymerase enzyme. ► Novel protocol to generate a structure-based pharmacophore using PLIF. ► Novel Knime workflow to generate virtual decoys. ► Novel method to achieve fast convergence in genetic function based docking. ► Discovery of new inhibitor bearing a new scaffold and its optimization.