title: Identification of a series of novel derivatives as potent HCV inhibitors by a ligand-based virtual screening optimized procedure.
abstract: This paper presents the results of a ligand-based virtual screening optimized procedure on 98 compounds which have been recently evaluated as inhibitors of genotype 1 HCV polymerase. First, quantitative structure-activity patterns are investigated for the selected compounds and then structural modifications are proposed to afford novel active patterns. An accurate and reliable QSAR model involving five descriptors that is able to predict successfully the HCV inhibitory potency against genotype 1 HCV polymerase is presented. Furthermore, the effects of various structural modifications on biological activity are investigated and biological activities of novel structures are estimated using the developed QSAR model. More specifically a search for optimized pharmacophore patterns by insertions, substitutions, and ring fusions of pharmacophoric substituents of the main building block scaffolds is described. The detection of the domain of applicability defines compounds whose estimations can be accepted with confidence.
authors.affiliation: School of Chemical Engineering, National Technical University of Athens, Athens, Greece.
authors.forename: Georgia
authors.initials: G
authors.lastname: Melagraki
authors.forename: Antreas
authors.initials: A
authors.lastname: Afantitis
authors.forename: Haralambos
authors.initials: H
authors.lastname: Sarimveis
authors.forename: Panayiotis A
authors.initials: PA
authors.lastname: Koutentis
authors.forename: John
authors.initials: J
authors.lastname: Markopoulos
authors.forename: Olga
authors.initials: O
authors.lastname: Igglessi-Markopoulou
mesh_terms: D001581:Benzothiadiazines / Q000737:chemistry / Q000494:pharmacology*; D003198:Computer Simulation; D016208:Databases, Factual; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008024:Ligands; D016014:Linear Models; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D013237:Stereoisomerism; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
chemical_list: D001581:Benzothiadiazines; D004791:Enzyme Inhibitors; D008024:Ligands; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase