title: Synthesis and in vitro evaluation of West Nile virus protease inhibitors based on the 1,3,4,5-tetrasubstituted 1H-pyrrol-2(5H)-one scaffold.
abstract: West Nile virus (WNV), a member of the Flaviviridae family, is a mosquito-borne pathogen that causes a large number of human infections each year. There are currently no vaccines or antiviral therapies available for human use against WNV. Therefore, efforts to develop new chemotherapeutics against this virus are highly desired. In this study, a WNV NS2B-NS3 protease inhibitor with a 1,3,4,5-tetrasubstituted 1H-pyrrol-2(5H)-one scaffold was identified by screening a small library of nonpeptidic compounds. Optimization of this initial hit by the synthesis and screening of a focused library of compounds with this scaffold led to the identification of a novel uncompetitive inhibitor ((-)-1a16, IC₅₀ =2.2±0.7 μM) of the WNV NS2B-NS3 protease. Molecular docking of the chiral compound onto the WNV protease indicates that the R enantiomer of 1a16 interferes with the productive interactions between the NS2B cofactor and the NS3 protease domain and is thus the preferred isomer for inhibition of the WNV NS2B-NS3 protease.
authors.affiliation: Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543.
authors.forename: Yaojun
authors.initials: Y
authors.lastname: Gao
authors.forename: Sanjay
authors.initials: S
authors.lastname: Samanta
authors.forename: Taian
authors.initials: T
authors.lastname: Cui
authors.forename: Yulin
authors.initials: Y
authors.lastname: Lam
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006168:Guinea Pigs; D062105:Molecular Docking Simulation; D010447:Peptide Hydrolases / Q000737:chemistry* / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014902:West Nile virus / Q000187:drug effects / Q000201:enzymology*
chemical_list: D011480:Protease Inhibitors; D011758:Pyrroles; D017361:Viral Nonstructural Proteins; D010447:Peptide Hydrolases
keywords: NS2B-NS3 protease; antiviral agents; bioorganic chemistry; docking studies; inhibitors