Abstract
NAMPT may represent a novel target for drug discovery in various therapeutic areas, including oncology and inflammation. Additionally, recent work has suggested that targeting NAMPT has potential in treating axon degeneration. In this work, publicly available X-ray co-crystal structures of NAMPT and the structures of two known NAMPT inhibitors were used as the basis for a structure- and ligand-based virtual screening campaign. From this, two novel series of NAMPT inhibitors were identified, one of which showed a statistically significant protective effect when tested in a cellular model of axon degeneration.
Keywords:
Axon degeneration; Molecular docking; NAMPT; Similarity searching; Virtual screening.
Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Axons / drug effects*
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Axons / metabolism
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Axons / pathology
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Caco-2 Cells
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Crystallography, X-Ray
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Cytochrome P-450 Enzyme System / metabolism
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Cytokines / antagonists & inhibitors*
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Cytokines / metabolism
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Dose-Response Relationship, Drug
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Drug Discovery*
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Humans
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Mice
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Mice, Nude
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Models, Molecular
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Molecular Structure
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Nicotinamide Phosphoribosyltransferase / antagonists & inhibitors*
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Nicotinamide Phosphoribosyltransferase / metabolism
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Cytokines
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Enzyme Inhibitors
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Cytochrome P-450 Enzyme System
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Nicotinamide Phosphoribosyltransferase
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nicotinamide phosphoribosyltransferase, human