title: Exploiting ChEMBL database to identify indole analogs as HCV replication inhibitors.
abstract: Molecular docking, 3D-QSAR CoMSIA and similarity search were combined in a multi-step framework with the ultimate goal to identify potent indole analogs, in the ChEMBL database, as inhibitors of HCV replication. The crystal structure of HCV RNA-dependent RNA polymerase (NS5B GT1b) was utilized and 41 known inhibitors were docked into the enzyme "Palm II" active site. In a second step, the docking pose of each compound was used in a receptor-based alignment for the generation of the CoMSIA fields. A validated 3D-QSAR CoMSIA model was subsequently built to accurately estimate the activity values. The proposed framework gives insight into the structural characteristics that affect the binding and the inhibitory activity of these analogs on HCV polymerase. The obtained in silico model was used to predict the activity of novel compounds prior to their synthesis and biological testing, within a Virtual Screening framework. The ChEMBL database was mined to afford compounds containing the indole scaffold that are predicted to possess high activity and thus can be prioritized for biological screening.
authors.affiliation: Department of Chemoinformatics, NovaMechanics Ltd., Nicosia, Cyprus; Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Athens 15771, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Vrontaki
authors.affiliation: Department of Chemoinformatics, NovaMechanics Ltd., Nicosia, Cyprus. Electronic address: melagraki@novamechanics.com.
authors.forename: Georgia
authors.initials: G
authors.lastname: Melagraki
authors.affiliation: Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Athens 15771, Greece.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mavromoustakos
authors.affiliation: Department of Chemoinformatics, NovaMechanics Ltd., Nicosia, Cyprus. Electronic address: afantitis@novamechanics.com.
authors.forename: Antreas
authors.initials: A
authors.lastname: Afantitis
mesh_terms: D062126:Databases, Chemical; D055808:Drug Discovery / Q000379:methods*; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D062105:Molecular Docking Simulation; D021281:Quantitative Structure-Activity Relationship; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors / Q000737:chemistry; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D007211:Indoles; D012324:RNA-Dependent RNA Polymerase
keywords: 3D-QSAR CoMSIA; ChEMBL database; HCV replication inhibitors; Molecular docking; Virtual Screening