Flaviviral protease inhibitors identified by fragment-based library docking into a structure generated by molecular dynamics.

Full Abstract

Fragment-based docking was used to select a conformation for virtual screening from a molecular dynamics trajectory of the West Nile virus nonstructural 3 protease. This conformation was chosen from an ensemble of 100 molecular dynamics snapshots because it optimally accommodates benzene, the most common ring in known drugs, and two positively charged fragments (methylguanidinium and 2-phenylimidazoline). The latter fragments were used as probes because of the large number of hydrogen bond acceptors in the substrate binding site of the protease. Upon high-throughput docking of a diversity set of 18,694 molecules and pose filtering, only five compounds were chosen for experimental validation, and two of them are active in the low micromolar range in an enzymatic assay and a tryptophan fluorescence quenching assay. Evidence for specific binding to the protease active site is provided by nuclear magnetic resonance spectroscopy. The two inhibitors have different scaffolds (diphenylurea and diphenyl ester) and are promising lead candidates because they have a molecular weight of about 300 Da.

Author information

Author/s: Ekonomiuk, Dariusz (D); Su, Xun-Cheng (XC); Ozawa, Kiyoshi (K); Bodenreider, Christophe (C); Lim, Siew Pheng (SP); Otting, Gottfried (G); Huang, Danzhi (D); Caflisch, Amedeo (A);

Affiliation: Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.

Journal and publication information

Publication Type: Journal Article

Journal: Journal of medicinal chemistry (J Med Chem), published in United States. (Language: eng)

Reference: 2009-Aug; vol 52 (issue 15) : pp 4860-8

Dates: Created 2009/09/01; Completed 2009/09/21;

PMID: 19572550, status: MEDLINE (last retrieval date: 9/21/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

RNA Helicases - antagonists & inhibitors; chemistry
Serine Endopeptidases - chemistry
Viral Nonstructural Proteins - antagonists & inhibitors; chemistry
West Nile virus - enzymology

Associated Chemicals: NS2B protein, flavivirus (0) ; NS3 protein, flavivirus (0) ; Protease Inhibitors (0) ; Viral Nonstructural Proteins (0) ; RNA Helicases (EC 2.7.7.-) ; Serine Endopeptidases (EC 3.4.21.-)

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