title: Inhibitors for the hepatitis C virus RNA polymerase explored by SAR with advanced machine learning methods.
abstract: Hepatitis C virus (HCV) is a global health challenge, affecting approximately 200 million people worldwide. In this study we developed SAR models with advanced machine learning classifiers Random Forest and k Nearest Neighbor Simulated Annealing for 679 small molecules with measured inhibition activity for NS5B genotype 1b. The activity was expressed as a binary value (active/inactive), where actives were considered molecules with IC50 ≤0.95 μM. We applied our SAR models to various drug-like databases and identified novel chemical scaffolds for NS5B inhibitors. Subsequent in vitro antiviral assays suggested a new activity for an existing prodrug, Candesartan cilexetil, which is currently used to treat hypertension and heart failure but has not been previously tested for anti-HCV activity. We also identified NS5B inhibitors with two novel non-nucleoside chemical motifs.
authors.affiliation: Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA. iweidlic@coddes.com
authors.forename: Iwona E
authors.initials: IE
authors.lastname: Weidlich
authors.forename: Igor V
authors.initials: IV
authors.lastname: Filippov
authors.forename: Jodian
authors.initials: J
authors.lastname: Brown
authors.forename: Neerja
authors.initials: N
authors.lastname: Kaushik-Basu
authors.forename: Ramalingam
authors.initials: R
authors.lastname: Krishnan
authors.forename: Marc C
authors.initials: MC
authors.lastname: Nicklaus
authors.forename: Ian F
authors.initials: IF
authors.lastname: Thorpe
mesh_terms: D000959:Antihypertensive Agents / Q000737:chemistry*; D000998:Antiviral Agents / Q000737:chemistry*; D001185:Artificial Intelligence; D001562:Benzimidazoles / Q000737:chemistry*; D001713:Biphenyl Compounds / Q000737:chemistry*; D062126:Databases, Chemical; D055808:Drug Discovery; D058492:Drug Repositioning; D016174:Hepacivirus / Q000737:chemistry / Q000201:enzymology; D062105:Molecular Docking Simulation; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012372:ROC Curve; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000737:chemistry*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000959:Antihypertensive Agents; D000998:Antiviral Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C077793:candesartan cilexetil